Abstract
Introduction
Familial Mediterranean fever (FMF) is an inherited autosomal recessive auto-inflammatory disorder characterized by recurrent episodes of fever and serositis, a condition marked by inflammation of the serous membranes enveloping diverse organs and body cavities. It frequently occurs among Turks, Armenians, Jews, and Arabs. The underlying genetic basis for FMF lies in mutations within the MEFV gene, situated on the short arm of chromosome 16. Given the absence of a definitive diagnostic test, diagnosis primarily relies on a comprehensive clinical evaluation and meticulous symptom assessment. The disease is characterized by intermittent inflammatory attacks that typically last 24 to 72 hours. Familial Mediterranean fever typically affects serous membranes, leading to manifestations such as pleuritis (or pleurisy, inflamed lining around the lungs), peritonitis (inflammation of the membranes of the abdominal wall), and synovitis (swollen or inflamed membrane of a joint). 1 One of the most severe long-term complications of FMF is amyloidosis, a buildup of abnormal protein deposits in various organs that can lead to organ dysfunction. Colchicine serves as the cornerstone pharmacotherapy for FMF, effectively preventing the onset of amyloidosis. 2
This case stands out due to its unique presentation of FMF in a pediatric patient. Parotitis, an uncommon extra-serosal manifestation of the disease, emerged as the initial presentation, followed by orchitis during a subsequent episode. Our literature review revealed no prior instances of parotitis as the inaugural presentation of FMF. This case highlights the critical importance of considering FMF in the differential diagnosis of atypical recurrent organ inflammation in pediatric patients, especially when encountering unusual clinical features. It underscores the need for a broad diagnostic perspective to ensure the timely and accurate recognition of FMF, even when its presentation deviates from conventional patterns.
Case Report
A healthy 4-year-old boy presented with a 2-day history of swelling, pain, and fever in the right parotid gland. Physical examination revealed a tender, enlarged right parotid gland, and ultrasonography confirmed parotitis. Other system examinations yielded no significant findings. Laboratory tests indicated an elevated white blood cell count (13 100/mm3), neutrophil count (9800/mm3), C-reactive protein (CRP) level of 151 mg/dL, and an erythrocyte sedimentation rate (ESR) of 45 mm/h. The patient’s other laboratory parameters were within normal limits. He was prescribed paracetamol and amoxicillin-clavulanate for symptomatic treatment. By the seventh-day follow-up, his symptoms had resolved, and the parotitis findings had completely disappeared. Approximately 1.5 months later, the patient returned with a 1-day history of pain, swelling in the left testis, and fever. Physical examination confirmed swelling in the left testis and fever. Laboratory results revealed a leukocyte count of 15 300 cells/mm3, a neutrophil count of 10 500 cells/mm3, an elevated CRP level of 178 mg/dL, an elevated ESR of 62 mm/h, and a fibrinogen level of 450 mg/dL. While the other laboratory parameters were within normal limits, the patient’s intermittent symptoms suggestive of an inflammatory disorder warranted a comprehensive family history evaluation. Given the recurrent inflammatory episodes, a detailed family history was obtained. It was discovered that the parents had third-degree consanguinity, and the patient’s aunt had a confirmed diagnosis of FMF. However, the patient had no history of abdominal pain, arthralgia, arthritis, or fever episodes. Familial Mediterranean fever was considered clinically; therefore, genetic analysis was performed. Hotspot mutation screening was performed with the FMF multiplex real-time polymerase chain reaction kit (SNP Biotechnology). A total of 20 mutations, which are common in exons 1, 2, 3, 5, and 10, were evaluated and the M694V homozygous mutation was detected in exon 10. The patient was prescribed a daily dose of 0.5 mg colchicine. During a 1-year follow-up, the patient reported no further episodes, demonstrating a positive response to treatment.
Discussion
Familial Mediterranean fever, an auto-inflammatory disorder, primarily affects the population from Mediterranean basin. 1 Turkey has a markedly higher incidence and prevalence of FMF compared with other regions. The clinical presentation of FMF is characterized by recurrent episodes of short-lived peritonitis, pleuritis, arthritis, rash, and fever. 3 A comprehensive study of FMF patients identified fever (81.9%), abdominal pain (86.3%), and myalgia (58.8%) as the most prevalent symptoms, while diarrhea (1.7%), prolonged febrile myalgia (1.2%), and acute orchitis (1.5%) were less commonly observed. 4 In our presented case, the patient’s sole manifestation was fever, aligning with a common presentation of FMF. Remarkably, this case represents the first documented instance, to the best of our knowledge, of a patient initially presenting with parotitis and subsequently receiving a diagnosis of FMF.
During FMF attacks, acute-phase reactants such as ESR, CRP, and fibrinogen levels typically rise and generally return to normal levels during symptom-free periods. 5 In our patient, the acute-phase reactants measured during the attack period were consistent with the elevated levels reported in the literature. This concordance suggests that the patient’s inflammatory response aligned with the expected pattern observed in FMF episodes.
A study involving 413 patients identified the homozygous M694V mutation as the most prevalent mutation, occurring in 24% of the cases. 6 In accordance with this finding, our patient also presented with the homozygous M694V mutation. Another study, encompassing 3505 FMF cases, reported that 400 patients developed amyloidosis. Among these patients with amyloidosis, 189 (47%) harbored the homozygous M694V mutation, a significantly higher frequency compared with FMF patients without amyloidosis (P < .0001). 7 Considering the presence of the homozygous M694V mutation in our patient, he was at an increased risk of developing amyloidosis.
Lifelong colchicine therapy is typically prescribed for FMF patients to prevent the long-term complication of AA amyloidosis and reduce the recurrence of febrile attacks. 8 The most common side effects associated with colchicine treatment include nausea, vomiting, and diarrhea. 9 It is important to note that long-term colchicine therapy may rarely lead to colchicine-induced myopathy and neuropathy, emphasizing the need for careful monitoring of patients receiving this medication. 10 For patients who are refractory to or intolerant of colchicine, interleukin-1 antagonists are considered the alternative treatment of choice. 11 In a study involving 62 children with FMF, colchicine administered at a daily dose of 0.5 to 1 mg yielded favorable outcomes. 12 Consistent with this, previous studies have demonstrated the effectiveness of colchicine in treating FMF, with response rates as high as 91.8% in Japanese FMF patients. 13 In our patient, we initiated a daily dose of 0.5 mg colchicine treatment. Over the course of a 1-year follow-up, no further attacks were reported, suggesting a positive response to treatment.
Conclusion
In regions with a high prevalence of FMF, maintaining a strong clinical suspicion for the disease is essential in patients presenting with recurrent organ involvement characterized by episodic attacks. The atypical findings observed in our case, including parotitis and orchitis, highlight the diverse and often unpredictable clinical manifestations. Prompt diagnosis and intervention are paramount to prevent severe complications, with amyloidosis being one of the most serious consequences. By recognizing and addressing FMF in a timely manner, health care providers can effectively mitigate the risk of long-term complications and improve patient outcomes.
Author Contributions
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
Our institution does not require ethical approval for reporting individual cases.
Informed Consent
Verbal and written consent was obtained. The written consent will be retained by the authors to protect confidentiality but will be available on request.
