Cachexia as an unusual presentation of familial Mediterranean fever: A case report

Abstract

BACKGROUND

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease, characterized by uncontrolled activation of the innate immune system that manifests as recurrent fever and polyserositis (e.g., peritonitis, pleuritis, and arthritis). However, diagnosing atypical cases remains challenging.

CASE SUMMARY

A 9-year-old girl had a history of progressive loss of appetite, weight loss, and myalgia over the preceding three months. She developed high-grade fever over the preceding three weeks, occasionally associated with abdominal pain. The girl is one of a triplet; neither of the other two sisters had similar symptoms. Family history was irrelevant. She presented with cachexia, generalized body aches, and fever without evident arthritis. She had splenomegaly and a markedly elevated erythrocyte sedimentation rate. After exclusion of rheumatological and malignant causes, FMF was suspected. Serum amyloid A was high. The patient received colchicine therapy. There was a significant improvement in her symptoms with normalization of acute-phase reactants. Polymerase chain reaction test for FMF gene mutation returned negative.

CONCLUSION

FMF can present with atypical symptoms. Detailed history and meticulous clinical evaluation were key clues suggesting the diagnosis.

Key Words: Atypical presentation; Cachexia; Familial Mediterranean fever; Myalgia; Case report

Core Tip: Familial Mediterranean fever is classically defined by recurrent episodes of spontaneous serositis with fever, but some children present with significant inflammation despite lacking these typical features. This case describes a 9-year-old girl with cachexia, debilitating myalgia, and recurrent fever, an atypical phenotype that created substantial diagnostic difficulty, especially with negative MEditerranean FeVer gene mutation testing. Her course underscores how familial Mediterranean fever may manifest beyond standard criteria and why clinicians must look beyond genetic results. A detailed history and careful clinical assessment were ultimately key to recognizing the disease.

INTRODUCTION

Familial Mediterranean fever (FMF), an autoinflammatory disease, is characterized by recurrent self-limiting attacks of fever, serositis, and arthritis, mostly seen in the mediterranean area. It is more common among Sephardic Jews, Armenians, Turks, and Arabs[1]. It is caused by autosomal recessive mutations in the MEditerranean FeVer (MEFV) gene, which encodes the pyrin protein[2]. Although the presence of mutations on both alleles helps to support the diagnosis, there is a need for sensitive and specific clinical criteria. There are three well-known and validated criteria: The Tel-Hashomer[3], Livneh criteria[4], and the pediatric Yalcinkaya-Ozen Turkish criteria[5]. In addition, the recent Eurofever/PRINTO classification criteria[6] have been evaluated in pediatric FMF patients[7,8].

Five sequence alterations [Met694Val, Val726Ala, Met680Ile (M680I), Met694Ile, and Glu148Gln], in the MEFV gene account for the majority of FMF mutations. Approximately 10%-20% of FMF patients do not carry any MEFV gene mutations[9]. However, failure to detect MEFV mutations does not rule out a diagnosis of FMF[10]. FMF may be typical or atypical, depending on clinical findings and genetic screening[11]. In atypical FMF cases, bouts of fever, for example, last for more than four days, and attacks of serositis present as localized and nonspecific symptoms, such as arthralgia and myalgia, are observed[12]. There are no specific hematological markers for atypical FMF; therefore, the diagnosis and initiation of treatment are often delayed[13]. The current report presents a 9-year-old girl with myalgia, cachexia, and recurrent fever.

CASE PRESENTATION

Chief complaints

A 9-year-old girl presented with intermittent high-grade fever, weakness, and easy fatigability for three weeks.

History of present illness

Symptoms started three weeks ago with intermittent high-grade fever, weakness, easy fatigability, and joint pains associated with anorexia and abdominal pain. She sought medical advice and was treated for infectious gastroenteritis, but with no improvement, she then presented to us.

History of past illness

Three months earlier, she had anorexia, abdominal pain, muscle pain, and marked loss of weight. She sought multiple medical consultations where investigations were requested to exclude malignant and autoimmune disorders like systemic lupus erythematosus and Juvenile idiopathic arthritis. Her acute phase reactants (APRs) were extremely elevated, and hemoglobin (Hb) was low. With no obvious clue, she received empirical antibiotics, but there was no improvement. Her attached investigations revealed elevated erythrocyte sedimentation rate (ESR) (120 mm/hour), low Hb (10 g/dL), and normal total leukocytic count (total leukocytic count = 8.400/mm³). Kidney function tests, rheumatoid factor, anti-nuclear antibody, and anti-double-stranded DNA were all negative.

Personal and family history

The girl was one of a triplet; neither of the other two sisters had similar symptoms. Family history was unremarkable.

Physical examination

She appeared cachectic, with a body weight of 22 kg (below 3^rd percentile), temperature 38.5 °C, with generalized body aches that worsened with movement, myalgia, splenomegaly, pallor, and tachycardia. There was no bone tenderness, no arthritis, or respiratory symptoms. There was no evident focus of infection.

Laboratory examinations

At presentation, complete blood count revealed decreasing Hb of 7.5 gm/dL, and ESR was 95/145 mm/hour. Urine analysis, Widal test, antistreptolysin O titer, and creatine phosphokinase were all normal.

Imaging examinations

Echocardiography was normal. An abdominal computed tomography scan was requested. There was splenomegaly and multiple nonspecific mesenteric lymph nodes with no features suggestive of malignancy.

FINAL DIAGNOSIS

At this time, for the unexplained recurrent fever lasting nearly two days, with her other symptoms (myalgia and abdominal pain) and elevated ESR, FMF was suspected. Serum amyloid A was 222 mg/L, and C-reactive protein (CRP) was 42 mg/L.

TREATMENT

Colchicine treatment was started at a dose of 0.03 mg/kg/day. Within one week, her symptoms began to improve.

OUTCOME AND FOLLOW-UP

After three weeks, her serological markers showed a remarkable decrease in ESR (14/30 mm/hour), CRP turned negative and Hb increased to 10 g/dL without any specific therapy for anemia. She continued colchicine therapy, and after six weeks, she had normal ESR and CRP. Hb increased to 12.9 g/dL without any supportive or specific therapy for anemia. Urinary albumin/creatinine ratio was 3.6 mg/g. After eight weeks, follow-up abdominal ultrasound revealed regression of splenomegaly. FMF- polymerase chain reaction (PCR) testing was performed and returned no identifiable mutation for the 12 conventional mutations tested. Her appetite partially improved, and she started to gain weight.

DISCUSSION

FMF is primarily a clinical diagnosis that is supported, when possible, by genetic testing[14]. Patients typically experience recurring attacks of fever and serositis with elevated APRs (CRP, ESR, serum amyloid A), leukocytosis, and neutrophilia. Although the disease is named fever, some patients may not experience fever[15]. Our patient presented with prolonged fever, loss of appetite, cachexia, and markedly elevated ESR. These clinical findings did not fit the pediatric FMF criteria. After excluding other possible etiologies, namely infection, malignancy, and rheumatological causes, the presence of intermittent fever and myalgia raised suspicion of FMF.

FMF is known to have a broad clinical spectrum. While musculoskeletal involvement, mostly in the form of arthritis or arthralgia, occur in nearly one-third of patients[16], muscular manifestations are less common but well recognized since first being described in 1945[17]. Severe debilitating myalgia, scrotal swelling, and cardiac involvement have also been reported[18]. In addition, Durmaz et al[19] reported a significant association between cachexia and FMF in females, which aligns with our patient’s presentation of cachexia and prolonged myalgia.

Genetic testing in Egypt employs PCR and reverse-hybridization for the identification of 12 mutations in the MEFV gene, namely Glu148Gln, Pro369Ser, Phe479 Leu, M680I (G/C), M680I (G/A), Ile692del, Met694Val, Met694Ile, Lys695Arg, Val726Ala, Ala744Ser, and Arg761His. Our patient tested negative for all, yet this did not preclude an FMF diagnosis. Response to colchicine therapy was remarkable. It is worth mentioning that the response to colchicine therapy is one of the major diagnostic parameters of Tel-Hashomer criteria[3].

Although FMF was originally defined as an autosomal recessive disorder, approximately 25% of the patients carry only one MEFV mutation[20], and 10%-20% carry no mutations at all[21]. In the Egyptian population, the rate of undetected mutation is even higher (56%) based on a study that included 1387 children with FMF[10]. Thus, the diagnosis of FMF still relies on clinical criteria, rather than genetic testing. Genetic analysis, if positive, supports the diagnosis in atypical presentations[22]. FMF patients with negative screening for common mutations may benefit from full MEFV gene sequencing, as additional pathogenic variants may be detected[23]. It is also possible that upstream or downstream defects in the pyrin pathway contribute to disease and explain PCR negativity[9].

CONCLUSION

Our reported case emphasizes that FMF needs to be considered even if the cardinal classical diagnostic criteria are not fulfilled. Uncommon and infrequent clinical symptoms of FMF may be the first presentation, especially when associated with evidence of inflammatory activity as reflected by elevated APRs. In addition, the absence of an identified gene mutation should not deter the diagnosis of FMF.