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Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disorder with typical early onset and recurrent episodes of fever and serositis. Late-onset FMF, especially presenting as isolated pleural effusion, is rare and often misdiagnosed. We present a case series of six patients over the age of 50 who were diagnosed with FMF after presenting with unexplained pleural effusions. Conventional evaluations failed to identify alternative etiologies, and empirical therapies showed limited success. In all cases, MEFV (Mediterranean fever) gene analysis revealed R202Q mutations, which guided the initiation of colchicine therapy with favorable outcomes. This study highlights the diagnostic challenges posed by atypical FMF presentations and underscores the importance of considering FMF in recurrent serositis, even without systemic inflammation. Early genetic testing and appropriate treatment may reduce unnecessary interventions and improve patient outcomes.

Plain language summary

A rare cause of pleural effusion in the lungs: Could it be familial Mediterranean fever?

Familial Mediterranean Fever (FMF) is a genetic disease that usually begins in childhood, causing repeated fever and inflammation in areas like the belly, chest, or joints. But in some rare cases, it can appear later in life with unusual symptoms. This study describes six older patients who developed fluid around their lungs (called pleural effusion) without clear causes like infection or cancer. After many tests, they were found to have mutations in a gene linked to FMF. All improved when treated with a medicine called colchicine, which helps control inflammation. These cases remind doctors to think about FMF even in older adults with lung symptoms and to use genetic testing when other diagnoses don’t fit. Early recognition can avoid unnecessary procedures and lead to better care.

Keywords

familial Mediterranean fever (FMF)R202Q mutation pleural effusion MEFV gene atypical presentation recurrent serositis colchicine therapy genome alterations

Introduction

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease,¹ predominantly affecting individuals of Mediterranean ancestry, including those of Turkish, Arab, Armenian, and Jewish descent. It is primarily inherited in an autosomal recessive manner, with mutations in the MEFV (Mediterranean fever) gene,¹ which encodes the pyrin protein. This defective protein dysregulates the innate immune response, leading to overexpression of interleukin-1β and recurring episodes of systemic inflammation.

Clinically, FMF is characterized by recurrent febrile episodes and serositis, manifesting as peritonitis, pleuritis, synovitis, and, less commonly, pericarditis.² These attacks typically begin before the age of 20 years, with early-onset disease being the most common presentation. While pleural effusion is a well-recognized manifestation of FMF, it is often overlooked when it occurs without other classic symptoms.³ In fact, pleural effusion and fever can be the sole manifestations in 5%-10% of patients, posing significant diagnostic challenges.⁴ Laboratory investigations during acute attacks may reveal evidence of systemic inflammation, characterized by leukocytosis and elevated levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, and serum amyloid A.⁵

Late-onset FMF, defined as disease onset after the fourth decade of life, is even more uncommon, accounting for only 2%-10% of all FMF cases. The diagnosis in these cases may be further delayed due to the atypical age of onset and the absence of a prior history of febrile or serositis episodes.⁶ This manuscript presents six cases of patients with pleural effusions who were ultimately diagnosed with late-onset FMF through genetic testing. Diagnosis was based on a comprehensive clinical evaluation incorporating elements from established FMF classification criteria combined with exclusion of alternative etiologies and gene confirmation. By highlighting these cases, we aim to emphasize the importance of considering late-onset FMF in the differential diagnosis of unexplained pleural effusions, especially in patients of Mediterranean ancestry or with suggestive clinical and laboratory findings.

Cohort cases

Case 1

A 68-year-old non-smoking woman presented to the emergency department with a 10-day history of shortness of breath and anorexia. She had undergone prior evaluation at another hospital, including computed tomography (CT) pulmonary angiography, which ruled out pulmonary embolism but revealed bilateral pleural effusion, a small pericardial effusion, and ground-glass opacities in the right lung. The patient reported four distinct episodes of pleural effusion over a 12-month period prior to diagnosis with each episode lasting approximately 2-3 days before spontaneous resolution. Abdominal CT showed gallstones without ascites. Initial laboratory workup demonstrated anemia (Hb 10.1 g/dL), elevated CRP (8 mg/dL; normal <0.5 mg/dL), and increased ESR (72 mm/h). Pleural ultrasound revealed bilateral anechoic pleural effusions with no internal septations, fibrinous strands, or pleural thickening. These findings were consistent with uncomplicated inflammatory effusions. Diagnostic thoracentesis revealed exudative pleural fluid with lymphocytic predominance (71%), pH 7.51, glucose 76 mg/dL, and adenosine deaminase (ADA) 22.3 U/L. Cytology and Gram stain were negative, ruling out malignancy and bacterial infection. The tuberculin skin test was also negative. Despite intravenous antibiotics (ceftriaxone) and supplemental oxygen for hypoxemia, the pleural effusion persisted. Further investigations excluded autoimmune and chronic infectious diseases, including anti-nuclear (ANA) and antineutrophil cytoplasmic (ANCA) antibodies, Epstein-Barr virus (EBV), cytomegalovirus (CMV), leptospirosis, and leishmaniasis. Gastroscopy performed for intermittent abdominal pain and pre-pyloric thickening identified mycosis and gastropathy, but stomach biopsies were negative. Given persistently elevated serum amyloid A levels (100 mg/L) and pleural and pericardial effusions, empirical colchicine therapy (1 mg/day) was initiated, and, although the patient denied any known family history of FMF, genetic testing was sent. Serial ultrasound assessments were used to monitor effusion regression following colchicine initiation. After 3 days, a chest X-ray also confirmed marked improvement in pleural effusion, and the patient was discharged. Genetic testing confirmed the diagnosis of FMF with homozygous mutation E148Q/E148Q and heterozygous alteration R202Q/0 in exon 2 of the MEFV gene.

Case 2

A 57-year-old man with a 40 pack-year smoking history presented to the emergency department with a 14-day history of fever and hypoxemic respiratory failure (pO₂ = 57 mmHg). His past medical history was notable for pancreatitis 6 years prior, and he reported no regular medication use. Additionally, over 8 months, the patient experienced three episodes of pleuritis, each resolving within 1-3 days. Laboratory evaluation revealed anemia (Hb 9.8 g/dL), elevated CRP (12.35 mg/dL; normal <0.5 mg/dL), increased ESR (106 mm/h), and elevated gamma-glutamyl transferase (119 U/L). Chest radiography showed blunting of the left costodiaphragmatic recess and an increased cardiothoracic ratio. Subsequent thoracic CT revealed left-sided pleural effusion, pericardial effusion, and ground-glass opacities in the right lower lobe. Thoracic ultrasound demonstrated a left-sided anechoic pleural effusion without evidence of septations, fibrinous strands, or pleural surface abnormalities. The effusion’s simple appearance supported an inflammatory etiology. Diagnostic thoracentesis demonstrated yellow exudative pleural fluid with lymphocytic predominance (55%), normal pH (7.40), glucose (82 mg/dL), and low ADA (11.1 U/L). Cultures and cytology were negative, ruling out malignancy and bacterial infection. The patient was treated empirically with intravenous ceftriaxone and moxifloxacin for suspected pneumonia and parapneumonic effusion, but his symptoms persisted. Further workup for autoimmune diseases, including tests for systemic lupus erythematosus and rheumatoid arthritis, as well as immunoglobulin levels, was unremarkable. Abdominal CT revealed no significant findings except for liver cysts. Tuberculin skin testing and blood cultures were negative. Given the presence of both pleural and pericardial effusions and elevated serum amyloid A (57.5 mg/L), colchicine and ibuprofen were initiated for suspected pericarditis, and genetic testing for FMF was sent, although no familial occurrence of FMF was documented. Genetic analysis revealed multiple polymorphisms and a heterozygous R202Q/0 alteration in exon 2 of the MEFV gene. Ultrasound was employed for follow-up evaluations to assess treatment response. On reappraisal 1 month later, cardiac and pulmonary ultrasounds showed a marked decrease in effusions. The patient had stopped ibuprofen and tolerated colchicine well without side effects.

Case 3

A 57-year-old man with a 40 pack-year smoking history was referred to our clinic for diagnostic thoracentesis following a routine chest X-ray performed 4 months earlier, which showed blunting of the left lateral costophrenic angle. From his medical history, two pleural effusion episodes developed within 4 months, each resolving in about 48 h. At the time of admission, the patient was asymptomatic, with no fever, shortness of breath, or chest pain. Ultrasound examination showed a moderate, unilocular anechoic left pleural effusion without septations, fibrinous deposits, or pleural thickening. These findings favored a non-infectious inflammatory process. Thoracentesis revealed a lymphocytic exudative pleural fluid with pH 7.42, glucose 74 mg/dL, and ADA 12.3 U/L. Cytology and cultures of the pleural fluid were negative, as were immunology tests and tumor markers. The patient was discharged with a recommendation for follow-up imaging in 2 weeks. Ten days later, the patient developed left-sided chest pain, prompting a CT pulmonary angiography. The scan ruled out pulmonary embolism but revealed marginally swollen right hilar lymph nodes, fibroatelectatic lesions in the lingula, and persistent left pleural effusion. An abdominal CT showed no pathological findings. As the pleural effusion remained undiagnosed, medical thoracoscopy was performed for pleural fluid drainage and parietal pleural biopsy. Cultures from pleural tissue samples were negative for pathogens, including Ziehl-Neelsen and Gram stains. Microscopic examination of the biopsy revealed nonspecific chronic inflammation. Follow-up with chest X-rays and hemithorax ultrasound showed no recurrence of pleural effusion for 2 years. However, the patient suddenly reported chest pain and low-grade fever (37.4°C) persisting for 2 weeks, accompanied by increased pleural effusion demonstrated by thoracic ultrasound. There was no reported history of FMF among the patient’s relatives. However, genetic testing for FMF was sent, which revealed a heterozygous alteration R202Q/0 in exon 2 of the MEFV gene. Colchicine therapy (1 mg/day in divided doses) was initiated without complications, resulting in a significant reduction of pleural effusion within 2 months.

Case 4

A 62-year-old woman with a 10 pack-year smoking history, referred by an external pulmonologist, presented with left-sided pleural effusion and ipsilateral atelectasis identified on chest CT. Her symptoms had begun 3 months prior with exertional dyspnea and dry cough that gradually worsened. Over these 3 months, the patient experienced three episodes of pleuritic chest pain, each lasting 1-3 days. Her medical history included arterial hypertension, dyslipidemia, hypothyroidism, osteoporosis, and pericarditis 1 year earlier. Upon admission, hemithorax ultrasound confirmed a significant left-sided pleural anechoic effusion, with no septations, fibrinous bands, or pleural surface irregularities observed. The imaging findings were compatible with an inflammatory effusion. Diagnostic thoracentesis revealed an exudative pleural fluid with a high percentage of polymorphonuclear leukocytes (67%), normal pH (7.45), glucose levels (87 mg/dL), ADA (19.1 U/L), and negative Gram stain and Ziehl-Neelsen stain. Laboratory tests showed leukocytosis (15.2 × 10⁶/μL) and elevated CRP (7.5 mg/dL; normal <0.5 mg/dL). The patient received intravenous ceftriaxone and metronidazole for 7 days for presumed parapneumonic effusion. Therapeutic thoracentesis was also performed, draining 1500 mL of pleural fluid. Post-procedure chest X-ray confirmed fluid reduction without pneumothorax. She was discharged on oral antibiotics (amoxicillin/clavulanic acid) for 7 days. At a follow-up chest X-ray 3 weeks later, pleural effusion had recurred, although the patient denied fever, cough, or chest pain. Further investigations for autoimmune diseases (ANA, ANCA, rheumatoid factor, C3, C4) and viral infections were unremarkable. Even though family history for FMF was negative, given her prior history of pericarditis and recurrent pleural effusion, genetic testing for FMF was conducted. The results revealed a heterozygous R202Q/0 alteration in exon 2 of the MEFV gene. The patient was started on colchicine (1 mg/day), which improved the pleural effusion but caused diarrhea. The colchicine dose was reduced to 0.5 mg/day, but within 2 weeks, the patient experienced left-sided chest pain, exertional dyspnea, and a recurrence of pleural effusion on chest X-ray. The colchicine dose was increased back to 1 mg/day, alongside dietary adjustments and probiotics to manage diarrhea. Serial ultrasound follow-ups documented effusion reduction after colchicine therapy. One month later, the pleural effusion had significantly reduced, and the patient reported no further symptoms, tolerating the treatment well.

Case 5

A 56-year-old woman with a 20 pack-year smoking history was referred to our clinic by an external pulmonologist due to fever and pleural effusion detected in the left hemithorax on chest CT. Her symptoms began 20 days prior, with chest pain, dry cough, and low-grade fever. She had received moxifloxacin for 7 days without significant improvement. The patient had no past medical history or prior hospitalizations. However, four chest pain episodes with arthralgia occurred over 14 months, typically resolving within 2-3 days with ibuprofen. Upon admission, hemithorax ultrasound confirmed a moderate left-sided pleural effusion without internal septations, fibrinous strands, or pleural thickening. The effusion was suggestive of an inflammatory cause rather than infectious or malignant. Diagnostic thoracentesis revealed exudative pleural fluid with polymorphonuclear neutrophil predominance (65%), normal pH (7.37), glucose (70 mg/dL), low ADA (11 U/L), and negative Gram stain and Ziehl-Neelsen stain. Laboratory exams showed leukocytosis (12.4 × 10⁶/μL) and elevated CRP (11.5 mg/dL; normal <0.5 mg/dL). She was treated with intravenous ceftriaxone and metronidazole for 7 days for presumed parapneumonic effusion. While her fever resolved, pleural effusion persisted, accompanied by worsening dyspnea. Therapeutic thoracentesis was performed, draining 1100 mL of pleural fluid. During her hospitalization, the patient reported pain in the joints of both hands. Immunological tests revealed a mildly elevated rheumatoid factor (18.9 mg/dL), ANA at 1:160, and negative anti-citrullinated protein antibodies. Hand X-rays showed no evidence of arthritis. Due to the combination of periodic fever, persistent pleural effusion, arthralgias, and elevated serum amyloid A (36 mg/L), genetic testing for FMF was performed. Although no familial predisposition to FMF was identified, the results revealed a heterozygous alteration R202Q/0 in exon 2 of the MEFV gene. Colchicine (1 mg/day) was initiated, resulting in significant improvement of pleural effusion and resolution of symptoms after 1 month. The patient reported remission of symptoms and good tolerance to colchicine, with no adverse effects during follow-up.

Case 6

A 64-year-old non-smoking woman presented to the emergency department with a 3-day history of dyspnea and left-sided chest pain. Her medical history included multiple sclerosis treated with rituximab and depression managed with escitalopram. Over the preceding 10 months, she had experienced three similar episodes of pleuritic chest pain, each lasting 2-3 days. Given her limited mobility due to multiple sclerosis, pulmonary embolism was systematically excluded during each presentation. The patient had no known relatives affected by FMF. On examination, she exhibited low oxygen saturation (91%), tachypnea, and elevated blood pressure (160/85 mmHg) but no fever. Laboratory results revealed leukocytosis, elevated liver enzymes (serum glutamic oxaloacetic transaminase 125 U/L, serum glutamate-pyruvate transaminase 153 U/L), and an increased CRP (11.6 mg/dL; normal <0.5 mg/dL). Chest X-ray showed blunting of the left costophrenic angle, and hemithorax ultrasound confirmed a left-sided anechoic pleural effusion, with a small contralateral effusion, both lacking septations, fibrinous strands, or pleural thickening. N-terminal prohormone of brain natriuretic peptide was elevated (950 pg/mL), but cardiac echocardiography did not support heart failure as the cause; it did, however, reveal a small pericardial effusion. Diagnostic thoracentesis of the left pleural effusion yielded orange, cloudy exudative fluid with lymphocyte predominance (58%), pH 7.45, glucose 75 mg/dL, and ADA 12.2 U/L. Pleural fluid cultures were negative. Further investigations for autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and vasculitis, were negative. Tests for immunoglobulin levels, thyroid function, and chronic infectious diseases were unremarkable. Elevated CA-125 (70 U/mL) prompted a gynecological evaluation, but no malignancy or pathology was identified. The patient also reported periodic abdominal pain over the past year; however, abdominal CT and gastroscopy with biopsies ruled out abdominal malignancy. The tuberculin skin test was negative. During hospitalization, the patient experienced worsening dyspnea, necessitating therapeutic thoracentesis, which drained 1000 mL of pleural fluid and improved oxygen saturation. She was discharged, but a follow-up chest X-ray after 3 weeks revealed recurrent left-sided pleural effusion. Cytological analysis of the pleural fluid demonstrated lymphocytes and eosinophils without malignant cells. Given the patient’s immunosuppressive treatment with rituximab, primary effusion lymphoma (PEL) was considered in the differential diagnosis. However, repeated cytological examinations and immunophenotyping of pleural fluid revealed no malignant cells, and testing for human herpesvirus-8 was negative, effectively excluding PEL. A thorough review of her medications, using Pneumotox, identified no drugs associated with pleural effusion. Given the recurrent pleural effusion and periodic abdominal pain, genetic testing for FMF was performed, revealing a homozygous R202Q polymorphism in exon 2 of the MEFV gene. Colchicine (1 mg/day) was initiated, leading to significant reduction in pleural effusion and resolution of symptoms after 1 month. Ultrasound was repeatedly used to monitor the evolution of pleural effusions and to guide clinical decision-making during follow-up.

Common learning points across all cases

FMF should be suspected in cases of unexplained recurrent pleural effusion, particularly when associated with serositis or systemic inflammatory features.

Chest ultrasound is valuable for characterizing pleural effusions and monitoring response to treatment, helping distinguish FMF-related effusions from infectious or malignant causes.

Early genetic testing can prevent unnecessary invasive procedures and prolonged empirical treatments.

Elevated serum amyloid A levels and nonspecific inflammatory markers often support the need for further genetic evaluation in atypical presentations.

Discussion

FMF is a genetically mediated autoinflammatory disorder with a diverse clinical spectrum. While it typically presents with fever and recurrent serositis, atypical manifestations, such as isolated pleural effusions, can complicate diagnosis, particularly in late-onset cases.⁷ These cases often lack systemic features like fever, further masking the disease and delaying diagnosis.⁸

In our cohort of patients with pleural effusion, genetic analysis was conducted when other diagnostic approaches failed to identify the etiology, and patients did not respond to conventional treatment. This reflects the recommended stepwise approach to undiagnosed pleural effusions, emphasizing structured diagnostic evaluation.⁹ Notably, none of the patients reported a family history of FMF, despite all belonging to a Mediterranean population (Greek origin) with high MEFV variant prevalence. Regarding clinical findings, all patients presented with pleural effusion, two exhibited typical abdominal symptoms, and three were found to have pericardial effusion. Chest ultrasound was essential in characterizing pleural effusions and guiding both diagnostic thoracentesis and follow-up monitoring. The simple sonographic appearance of effusions, lacking septations or pleural thickening, supported an autoinflammatory process rather than infectious or malignant causes.¹⁰ Additionally, fever was reported in three patients, while one patient complained of arthralgia. Although pleural fluid in FMF is often described as an exudate with predominance of polymorphonuclear cells, lymphocyte-predominant effusions have also been reported, including well-documented cases of lymphocytic pleuritis.^8,11 Serum amyloid A demonstrated a strong correlation with FMF attacks, serving as the most sensitive marker for detecting subclinical inflammation during attack-free periods.¹² Elevated serum amyloid A levels were noted in half of our patients, offering supportive inflammatory evidence that complemented the clinical and genetic findings suggestive of FMF (Table 1).

Table 1.

Clinical manifestations and laboratory findings in patients consistent with a diagnosis of familial Mediterranean fever.

Patient	Fever	Pericarditis	Pleural effusion	Arthritis	Abdominal pain	Serum amyloid A
1	−	−	+	−	+	+
2	+	+	+	−	−	+
3	+	−	+	−	−	−
4	−	+	+	−	−	−
5	+	−	+	+	−	+
6	−	+	+	−	+	−

Genetic analysis revealed that the most common allele alteration in our cohort was the R202Q mutation in exon 2 of the MEFV gene, which was identified in five patients in a heterozygous state and in one patient in a homozygous state. Clinical features such as recurrent serositis and chest pain were evaluated alongside genetic findings and colchicine response, integrating these elements to support the diagnosis despite the lack of definitive evidence supporting R202Q heterozygosity as a pathogenic variant.¹³

The differentiation between FMF and idiopathic recurrent serositis (IRS) remains a recognized diagnostic challenge, particularly in atypical cases presenting with isolated serosal involvement and low-penetrance MEFV variants like in our cohort. Recent studies have underscored the relevance of Non-specific Pleuritis as the histopathological correlation of IRS in patients with recurrent serositis lacking definitive genetic confirmation.^14,15 In our cohort, however, the identification of MEFV gene alterations, even a low-penetrance variant such as the R202Q, and a favorable response to colchicine guided the diagnosis toward FMF. Although R202Q has traditionally been regarded as a benign polymorphism, recent literature suggests its potential role as a phenotypic modifier contributing to atypical FMF manifestations, particularly in Mediterranean populations.¹⁶ We acknowledge the clinical overlap between IRS and atypical FMF, which may represent a continuum rather than distinct entities.¹⁷ It is also conceivable that not all pathogenic MEFV variants have been fully identified, and that complex genetic interactions, such as modifier variants or a potential two-hit mechanism, may contribute to these atypical clinical presentations.¹⁸ Nevertheless, given the genetic predisposition, consistent clinical patterns, and documented therapeutic response, we consider the classification of these cases as atypical FMF to be more appropriate and clinically meaningful. Classifying these patients as IRS could underestimate the underlying genetic contribution and potentially overlook the benefits of colchicine therapy in this population.

Similar diagnostic dilemmas have been reported across the Mediterranean basin, where FMF cases harboring the low-penetrance R202Q variant often present with recurrent serositis or isolated pleural effusions. To contextualize these observations, previously published FMF cases and cohorts with the R202Q mutation are summarized in Table 2. Collectively, these data demonstrate that R202Q-positive FMF often manifests with localized, serositis-dominant inflammation and a favorable response to colchicine, aligning with the clinical profile observed in our series.

Table 2.

Previously reported FMF cases and cohorts harboring the R202Q variant.

Author (year)	Country	Study type	R202Q genotype	Main clinical presentation
Katsenos et al. (2008)⁸	Greece	Case report	Homozygous R202Q (+ D102D, A165A)	Recurrent febrile pleuritis with unilateral lymphocytic effusion; complete colchicine response
Yigit et al. (2012)¹³	Turkey	Case–control cohort (191 FMF patients/150 controls)	Homozygous and heterozygous R202Q carriers	Typical FMF attacks (fever, serositis); R202Q significantly more frequent in patients
Comak et al. (2014)¹⁹	Turkey	Pediatric FMF cohort (n = 225)	55 het, 30 homo R202Q (± compound)	Recurrent fever and abdominal pain; R202Q homozygotes showed milder phenotype
Çankaya (2015)²⁰	Turkey	Pediatric FMF cohort (n = 115)	15 homo R202Q (≈66% carriers)	FMF in children; isolated R202Q associated with mild symptoms and good colchicine response
Erdem et al. (2018)²¹	Turkey	Case report	Homozygous R202Q	Adult with recurrent fever and peritonitis; complete response to colchicine
Arpacı et al. (2021)²²	Turkey	Regional genetic survey of FMF (n = 2639)	R202Q most frequent allele (19.5%); homozygotes present	FMF mutation spectrum study; R202Q dominant variant regionally
Kandur et al. (2022)²³	Turkey	Clinical cohort study	Compound heterozygotes M694V/R202Q and others	FMF with arthritis-dominant phenotype; R202Q considered clinically relevant
Sgouropoulou et al. (2022)²⁴	Greece	Retrospective NGS analysis (n = 31)	R202Q in 61.3% of patients	FMF patients with atypical phenotypes; NGS confirmed diagnosis and revealed high R202Q frequency
Di Ciaula et al. (2023)²⁵	Italy	Adult FMF cohort (n = 147)	R202Q in 41.6% of MEFV variants	Classical FMF manifestations (fever, serositis, arthralgia); mild phenotype in R202Q carriers
Dimeas et al. (2023)⁶	Greece	Case report	Heterozygous R202Q	FMF presenting as painless massive pleural effusion; favorable colchicine response
Çapraz and Düz (2023)²⁶	Turkey	Large retrospective cohort (n = 1570)	R202Q in 36% (het and homo)	Clinically diagnosed FMF; high R202Q prevalence in Central Black Sea region
Andreis et al. (2024)²⁷	Italy	Case report (FMF-like autoinflammation)	Homozygous R202Q	Recurrent pericarditis responsive to anakinra; FMF-like phenotype
Sagris et al. (2025)¹⁶	Greece	FMF cohort study	Homozygous R202Q predominant	Atypical FMF phenotype with later onset and mild serositis; linked to R202Q homozygosity
Baggio et al. (2025)²⁸	Italy	Functional/mechanistic study	11 heterozygous (61%) and 7 homozygous (39%) R202Q	FMF-like inflammation and neutrophil nuclear abnormalities similar to FMF patients
Gharibi et al. (2025)²⁹	Iran	Cohort (n = 416 FMF patients)	R202Q allele 39.9% (most common variant)	Classical FMF symptoms (fever, serositis, arthralgia, vomiting); R202Q predominant variant in NW Iran

FMF: familial Mediterranean fever; het: heterozygous; homo: homozygous; NGS: next-generation sequencing.

Building on these observations, our study provides implications for the role of the R202Q mutation in the MEFV gene as a potent driver of atypical FMF phenotypes, particularly recurrent pleuritis and undiagnosed pleural effusions.²³ Traditionally regarded as a low-penetrance polymorphism associated with milder disease, R202Q has gained attention as a significant contributor to distinct inflammatory phenotypes.²⁰ In our cohort, all six patients presented with recurrent pleural effusions, with five harboring the R202Q mutation in a heterozygous state and one in a homozygous state. These findings suggest that R202Q could act as a potent modifier, driving localized inflammation in the pleural cavity, unlike high-penetrance exon 10 mutations, such as M694V, which often lead to systemic inflammatory responses.²⁴ The observations in our cohort support its association with pleuritis, aligning with prior studies that identify chest pain as a hallmark feature in R202Q-positive patients.³⁰ This putative tissue-specific inflammatory response driven by R202Q highlights the need for genotype-specific approaches to diagnosis and management.

The molecular basis of the R202Q mutation lies in its impact on the pyrin protein, which regulates the inflammasome and interleukin-1β production. Recent hypotheses suggest that R202Q may impair pyrin’s regulation of caspase-1 activation, leading to localized overproduction of interleukin-1β.³¹ This dysregulation may explain the pleuritic and serosal inflammation observed in this cohort, particularly in the absence of fever or widespread inflammation. Further studies are needed to elucidate the precise molecular mechanisms by which R202Q modulates these inflammatory pathways, as such insights could inform targeted therapeutic strategies.

The variability in clinical presentation among R202Q-positive patients also raises the possibility of environmental or epigenetic factors influencing disease expression.³² Triggers such as infections, emotional stress, or inflammatory stimuli may exacerbate localized inflammatory responses, potentially accounting for the episodic nature and irregular intervals of symptoms observed in this cohort. Nevertheless, the clinical significance of R202Q remains a subject of ongoing debate, with some studies considering it a benign polymorphism without clear pathogenicity.¹³ Its phenotypic impact is likely context-dependent, influenced by genetic background, modifier genes, and environmental exposures, underscoring the need for individualized assessment when interpreting R202Q findings in clinical practice.³³

Previous studies have highlighted the challenges of timely FMF diagnosis, even in regions with high FMF prevalence, with approximately 20% of patients experiencing diagnostic delays exceeding 10 years.³⁴ In our cohort, the time from the first clinical manifestation to genetic confirmation ranged from 35 to 750 days (Figure 1). The diagnosis of FMF in atypical and late-onset presentations is inherently challenging, as reflected in previous studies, where diagnostic delays have been reported to range from 35 to 390 days.³⁴ Our findings extend this observation, demonstrating even longer delays in certain cases due to atypical clinical presentations. Traditional diagnostic approaches often focus on systemic inflammation, which may not be prominent in R202Q-positive cases.²⁷ In this cohort, genetic analysis proved pivotal, identifying the mutation as the underlying cause of inflammation after extensive workups for alternative etiologies failed. Incorporating MEFV gene testing early in the diagnostic workflow for patients presenting with recurrent pleuritis or unexplained pleural effusions may improve diagnostic efficiency and outcomes.³⁵ Advances in next-generation sequencing technologies offer cost-effective opportunities for comprehensive genetic screening, enabling earlier identification of R202Q and other low-penetrance variants in populations with atypical presentations.^1,7

Figure 1.

Duration from the onset of familial Mediterranean fever symptoms to the final diagnosis.

The potential role of R202Q as a significant contributor to atypical FMF phenotypes suggests that genetic screening could be valuable in selected clinical contexts. In high-prevalence populations, targeted screening programs may facilitate earlier diagnosis, help reduce complications, and potentially improve quality of life. Furthermore, the putative localized inflammatory patterns associated with R202Q suggest that other low-penetrance variants in autoinflammatory genes may similarly drive tissue-specific phenotypes. These insights could extend beyond FMF to inform the management of other monogenic inflammatory conditions, such as TNF receptor-associated periodic syndrome and cryopyrin-associated periodic syndrome, where tissue-specific phenotypes driven by low-penetrance mutations are similarly observed.²⁰

In our cohort, colchicine was initiated empirically in two patients on the same day that genetic testing was ordered, guided by high clinical suspicion after exclusion of infectious, malignant, and autoimmune causes. The remaining four patients were started on colchicine following genetic confirmation of MEFV alterations. While a favorable response to colchicine is considered a major diagnostic criterion in the Tel Hashomer criteria,³⁶ it is not mandatory for establishing an FMF diagnosis, particularly in atypical cases. Importantly, these criteria have not been validated in late-onset or atypical presentations such as isolated pleural effusion in older adults. Furthermore, the newer Eurofever/PRINTO classification criteria³⁷ do not include colchicine responsiveness, instead emphasizing the presence of confirmatory MEFV genotypes and clinical features such as chest pain, abdominal pain, arthritis, and duration of episodes. In our cohort, all patients met these clinical parameters. Given the rare occurrence of isolated pleural effusion as a primary FMF manifestation in this age group, empirical colchicine therapy was employed pragmatically to control symptoms and support diagnostic evaluation. We acknowledge the potential for retrospective attribution bias; however, colchicine was introduced only after comprehensive clinical assessment, with genetic confirmation subsequently supporting the diagnosis. This raises the question of whether systematic testing for MEFV mutations in patients with unexplained, recurrent nonspecific pleuritis could reveal underrecognized cases of atypical FMF.¹⁶

Although our R202Q-linked case series focuses on patients with documented pleural effusion, similar thoracic serositis has been described across different MEFV genotypes. Beyond R202Q, isolated pleural effusion or pleuritis-dominant FMF has been reported with high-penetrance exon-10 variants such as M694I/M694I³⁸ and M680I/M680I.³⁹ Furthermore, several studies have documented pleuritic or chest pain as the predominant presentation of FMF, even when pleural effusion was not radiologically confirmed. These include patients carrying M694V/M694V and other exon-10 variants⁴ as well as pediatric cohorts where E148Q, in exon 2, was associated with recurrent chest-pain episodes.^40,41 Given that imaging was not systematically performed in many of these series, it is plausible that some “pleuritic-pain” episodes could reflect subclinical pleural effusion, raising the possibility of a shared pyrin-mediated pleural-inflammation spectrum rather than a mutation-specific phenotype.

Therapeutically, colchicine remains the cornerstone of FMF management, effectively reducing the frequency and severity of attacks while preventing complications such as amyloidosis.⁴² In this study, all patients were initiated on colchicine following genetic confirmation, with four achieving complete symptom resolution. However, two patients exhibited colchicine resistance, necessitating alternative therapies. For these patients, an interleukin-1 receptor antagonist, such as anakinra, could be beneficial,²⁴ highlighting the importance of personalized treatment plans. However, challenges such as the cost and limited availability of interleukin-1 inhibitors may restrict their widespread use, underscoring the need for further research to identify additional therapeutic options.

This study has several limitations inherent to its retrospective case series design. Firstly, the small sample size limits the generalizability of the findings to larger populations. Secondly, although all patients underwent extensive diagnostic workups, the clinical significance of the R202Q variant remains debated, given its low penetrance and high prevalence in the general population. Nonetheless, alternative diagnoses were systematically excluded through targeted investigations. Furthermore, the empirical initiation of colchicine was based on clinical suspicion of FMF and is aligned with established diagnostic frameworks, such as the Tel Hashomer criteria, which recognize colchicine response as a supportive diagnostic feature. Despite these limitations, the consistent clinical presentation of late-onset pleural effusion and the favorable response to colchicine across the cohort underscore the importance of considering the R202Q polymorphism as a potential driver of FMF in cases of unexplained recurrent pleural effusions.

Future research should focus on longitudinal studies to evaluate the long-term outcomes of R202Q-positive patients, particularly their risk of complications such as amyloidosis. Additionally, investigating the efficacy of novel therapies, including targeted interleukin-1 inhibitors, could refine treatment strategies. Mechanistic studies are needed to clarify the pathways by which R202Q modulates inflammation, potentially uncovering new targets for intervention. Collaborative efforts between clinicians and genetic researchers may also help elucidate the role of environmental and epigenetic factors in modifying disease expression.

Conclusion

This study highlights the diagnostic challenges posed by atypical presentations of FMF, particularly in cases of recurrent pleuritis and pleural effusions. In our cohort of six patients, the presence of the R202Q mutation in the MEFV gene was pivotal in confirming FMF as the underlying cause, following extensive workups that failed to identify alternative etiologies. These findings emphasize the need for heightened clinical awareness of FMF as a potential diagnosis in patients with unexplained recurrent serositis, especially pleuritis, even in the absence of systemic features such as fever. Early consideration of FMF, supported by genetic testing, can prevent unnecessary invasive diagnostic procedures and reduce delays in reaching a definitive diagnosis. Clinicians should maintain a high index of suspicion for FMF in such cases, ensuring timely and accurate diagnosis to improve patient outcomes and avoid diagnostic pitfalls.

Supplemental Material

sj-docx-1-taj-10.1177_27558428251412568 – Supplemental material for Late-onset familial Mediterranean fever: A case series of missed diagnoses in pleural effusions

Supplemental material, sj-docx-1-taj-10.1177_27558428251412568 for Late-onset familial Mediterranean fever: A case series of missed diagnoses in pleural effusions by Angeliki Miziou, Ilias E. Dimeas, Romanos Ntiloudis, Charalampos Varsamas and Konstantinos I. Gourgoulianis in Therapeutic Advances in Chronic Disease

Footnotes

Acknowledgements

The authors thank the patients and colleagues who contributed to the clinical evaluations.

ORCID iD

Ilias E. Dimeas

Ethical considerations

This is a retrospective case series of anonymized data with no experimental intervention. According to institutional policies of the University Hospital of Larissa, ethical approval was not required.

Consent for publication

Written informed consent for publication of anonymized clinical data was obtained from all patients.

Author contributions

Angeliki Miziou: Conceptualization; Data curation; Formal analysis; Writing-original draft; Writing-review & editing.

Ilias E. Dimeas: Conceptualization; Data curation; Formal analysis; Writing-original draft; Writing-review & editing.

Romanos Ntiloudis: Data curation; Investigation; Writing-original draft.

Charalampos Varsamas: Investigation; Supervision; Writing-review & editing.

Konstantinos I. Gourgoulianis: Conceptualization; Supervision; Writing-review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data analyzed during the current study are available from the corresponding author on reasonable request.*

Supplemental material

Supplemental material for this article is available online.

References

Sarı

Birlik

Kasifoğlu

. Familial Mediterranean fever: an updated review. Eur J Rheumatol 2014; 1(1): 21–33.

Shohat

Halpern

GJ.

Familial mediterranean fever—a review. Genet Med 2011; 13(6): 487–498.

Özsu

Özçelik

Bülbül

Familial Mediterranean fever is a rare cause of recurrent pleural effusion. Respir Case Rep 2013; 2(3): 143–146.

Sever

Sanal

, et al Yalnız pulmoner bulguları olan ailesel Akdeniz ateşi; genetik analizle erken tanı [Familial Mediterranean fever with pulmonary manifestations alone; early diagnosis with genetic analysis]. Tuberk Toraks 2012; 60(4): 380–384.

Meyerhoff

JM.

Familial Mediterranean fever workup: Laboratory studies, genetic testing, imaging studies. Medscape, https://emedicine.medscape.com/article/330284-workup (2024, accessed 7 April 2025).

Dimeas

Papacharalampous

, et al Familial Mediterranean fever in a 28-year-old male presented as a painless massive pleural effusion. Cureus 2023; 15(7): e41776.

Kim

Ikusaka

Mikasa

, et al Clinical study of 7 cases of familial Mediterranean fever with MEFV gene mutation. Intern Med 2007; 46(5): 221–225.

Katsenos

Mermigkis

Psathakis

, et al Unilateral lymphocytic pleuritis as a manifestation of familial Mediterranean fever. Chest 2008; 133(4): 999–1001.

Panjwani

Salman

MR.

An uncommon cause of pleural effusion. Breathe (Sheff) 2019; 15(2): e84–e89.

10.

Koegelenberg

Irusen

von Groote-Bidlingmaier

, et al The utility of ultrasound-guided thoracentesis and pleural biopsy in undiagnosed pleural exudates. Thorax 2015; 70(10): 995–997.

11.

Sohar

Gafni

Pras

, et al Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967; 43(2): 227–253.

12.

Çakan

Karadağ

Tanatar

, et al The value of serum amyloid A levels in familial Mediterranean fever to identify occult inflammation during asymptomatic periods. J Clin Rheumatol 2019; 27(1): 1–4.

13.

Yigit

Karakus

Tasliyurt

, et al Significance of MEFV gene R202Q polymorphism in Turkish familial Mediterranean fever patients. Gene 2012; 506(1): 43–45.

14.

Janssen

Maldonado

Metintas

What is the significance of non-specific pleuritis? A trick question. Clin Respir J 2018; 12(9): 2407–2410.

15.

Wrightson

Davies

HE.

Outcome of patients with nonspecific pleuritis at thoracoscopy. Curr Opin Pulm Med 2011; 17(4): 242–246.

16.

Sagris

Antoniadou

Gatselis

, et al R202Q homozygosity of Mediterranean fever gene is associated with atypical clinical phenotype of familial Mediterranean fever. Eur J Intern Med 2025; 138: 69–75.

17.

Massaro

Rigante

Sicignano

, et al Therapeutic management of idiopathic recurrent serositis: a retrospective study. Eur Rev Med Pharmacol Sci 2020; 24(6): 3352–3359.

18.

Touitou

The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 9(7): 473–483.

19.

Comak

Akman

Koyun

, et al Clinical evaluation of R202Q alteration of MEFV genes in Turkish children. Clin Rheumatol 2014; 33(12): 1765–1771.

20.

Çankaya

Clinical significance of R202Q alteration of MEFV gene in children with familial Mediterranean fever. Arch Rheumatol 2015; 30(1): 51–56.

21.

Erdem

Saritas

Karaali

, et al A rare cause of fever in an adult: a case of familial Mediterranean fever. Int Med Case Rep J 2018; 11: 37–40.

22.

Arpacı

Doğan

Erdoğan

, et al Presentation of a new mutation in FMF and evaluating the frequency of distribution of the MEFV gene mutation in our region with clinical findings. Mol Biol Rep 2021; 48(3): 2025–2033.

23.

Kandur

Kocakap

DBS

Alpcan

, et al Clinical significance of MEFV gene variation R202Q. Clin Rheumatol 2021; 41(1): 271–274.

24.

Sgouropoulou

Farmaki

Papadopoulos

, et al Sequence analysis in familial Mediterranean fever patients with no confirmatory genotype. Rheumatol Int 2022; 42(1): 15–22.

25.

Di Ciaula

Iacoviello

Bonfrate

, et al Genetic and clinical features of familial Mediterranean fever (FMF) in a homogeneous cohort of patients from South-Eastern Italy. Eur J Intern Med 2023; 115: 79–87.

26.

Çapraz

Düz

ME.

R202Q prevalence in clinically diagnosed Familial Mediterranean Fever patients: 9 years of data analysis from 1570 patients living Central Black Sea region, Turkey. Ir J Med Sci 2023; 192(5): 2273–2278.

27.

Andreis

Dossi

De Ferrari

, et al Anakinra-dependent recurrent pericarditis: the role of the R202Q variant of the MEFV gene. J Clin Med 2024; 13(20): 6051.

28.

Baggio

Oliviero

Galozzi

, et al

Unresolved issues in familial Mediterranean fever: is p.R202Q MEFV variant potentially pathogenetic in unleashing inflammation?

J Clin Immunol 2025; 45(1): 104.

29.

Gharibi

Babaei

Vahabi

Screening of the most common MEFV variants in 416 patients of familial Mediterranean fever living in Northwest of Iran. J Adv Pharm Technol Res 2025; 16(1): 12–17.

30.

Sönmezgöz

, et al Clinical and demographic evaluation according to MEFV genes in patients with familial Mediterranean fever. Biochem Genet 2018; 57(2): 289–300.

31.

Yilmaz

Ozer

Ozyurt

, et al Familial Mediterranean fever gene mutations in the inner northern region of Turkey and genotype–phenotype correlation in children. J Paediatr Child Health 2009; 45(11): 641–645.

32.

Zekry

Sallam

AbdelHamid

, et al Genetic and epigenetic regulation of MEFV gene and their impact on clinical outcome in auto-inflammatory familial Mediterranean fever patients. Curr Issues Mol Biol 2023; 45(1): 721–737.

33.

Karakus

Yigit

Inanir

, et al Association between sequence variations of the Mediterranean fever gene and fibromyalgia syndrome in a cohort of Turkish patients. Clin Chim Acta 2012; 414: 36–40.

34.

Bourguiba

Deshayes

Amaryan

, et al Diagnostic delays in familial Mediterranean fever: a Juvenile Inflammatory Rheumatism (JIR) cohort study. Rheumatol Int 2024; 44(12): 3107–3111.

35.

Sönmez

Batu

Özen

Familial Mediterranean fever: current perspectives. J Inflamm Res 2016; 9: 13–20.

36.

Livneh

Langevitz

Zemer

, et al Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40(10): 1879–1885.

37.

Gattorno

Hofer

Federici

, et al Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 2019; 78(8): 1025–1032.

38.

Lega

Khouatra

Cottin

, et al Isolated recurrent pleuritis revealing familial Mediterranean fever in adulthood. Respiration 2010; 79(6): 508–510.

39.

Mejri

Saidane

Boubaker

, et al A recurrent side-changing febrile pleural effusion revealing familial Mediterranean fever: a case report. Pan Afr Med J 2022; 43: 121.

40.

Sunar-Yayla

Şenol

Yıldırım

, et al Chest pain in children with familial Mediterranean fever. Turk J Pediatr 2023; 65(6): 973–979.

41.

Tirosh

Yacobi

Vivante

, et al Clinical significance of E148Q heterozygous variant in paediatric familial Mediterranean fever. Rheumatology (Oxford) 2021; 60(11): 5447–5451.

42.

Ozen

Demirkaya

Erer

, et al EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016; 75: 644–651.

Supplementary Material

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Patient	Fever	Pericarditis	Pleural effusion	Arthritis	Abdominal pain	Serum amyloid A
1	−	−	+	−	+	+
2	+	+	+	−	−	+
3	+	−	+	−	−	−
4	−	+	+	−	−	−
5	+	−	+	+	−	+
6	−	+	+	−	+	−

Patient	Fever	Pericarditis	Pleural effusion	Arthritis	Abdominal pain	Serum amyloid A
1	−	−	+	−	+	+
2	+	+	+	−	−	+
3	+	−	+	−	−	−
4	−	+	+	−	−	−
5	+	−	+	+	−	+
6	−	+	+	−	+	−

Patient	Fever	Pericarditis	Pleural effusion	Arthritis	Abdominal pain	Serum amyloid A
1	−	−	+	−	+	+
2	+	+	+	−	−	+
3	+	−	+	−	−	−
4	−	+	+	−	−	−
5	+	−	+	+	−	+
6	−	+	+	−	+	−