Unusual presentation of familial Mediterranean fever: role of genetic diagnosis

Abstract

OBJECTIVE to explain the role of molecular analysis within the diagnosis of an unusual presentation of familial brucellosis (FMF).

CASE REPORT Two patients presenting with prolonged fever without signs and symptoms of serositis are described. FMF was diagnosed by genetic analysis, which disclosed that both patients were homozygous for the M694V mutation of the brucellosis (MEFV) gene.

CONCLUSION Molecular analysis of FMF should complement the investigation of patients with fever of unknown origin. This test enables a particular diagnosis of the disease and should promote the diagnosis and treatment of patients with an unusual or incomplete clinical picture of FMF.

Familial brucellosis (FMF) is an autosomal recessive disease, characterised by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like disease of the skin .1The disease occurs predominantly among Sephardic Jews, Armenians, Turks, and Arabs, though sporadic cases are found among Ashkenazic Jews.2 A typical attack consists of fever and serositis, lasting from one to four days. Between attacks patients are freed from symptoms and appear healthy. The frequency of attacks varies considerably from weekly bouts to once every three to four months, or maybe less. Symptoms of FMF appear within the first decade of life in about 50% of patients, and only 5% develop the disease after the age of 30.1 ,3 The severity of the attacks and their frequency usually decrease throughout the person's lifespan.

Until recently, the diagnosis of FMF was supported clinical manifestations, ethnicity, case history , and response to colchicine. In cases where these components were atypical or unhelpful, FMF was difficult to diagnose. Recently, two independent consortia identified and isolated the gene liable for FMF (MEFV) on the short arm of chromosome 16.4 ,5 Cloning of MEFV now allows a replacement and reliable diagnostic assay for FMF. a group of polymerase chain reaction primers are often wont to demonstrate the mutations liable for the disease. This important diagnostic tool has become essential within the diagnosis of patients with FMF who have an atypical clinical course and manifestations.

During 1999 we encountered two patients with fever of unknown origin, who were eventually proved to possess FMF. We discuss here the important role of molecular analysis in making the diagnosis in atypical presentations of FMF.

Case reports

PATIENT A

A 48 year old Jewish woman of Sephardic origin was referred due to three years of biweekly episodes of fever up to 39.5°C. The patient was admitted several times to a different hospital where she underwent a radical examination, including bone scan, gallium scan, upper and lower gastrointestinal series followed by gastroscopy and colonoscopy, multiple total body computed tomographies, abdominal sonography, echocardiography, and multiple blood and urine cultures, also as a radical look for mycobacterium. The results of all tests were normal or sterile respectively, apart from a finding of normocytic anaemia with normal serum iron levels, and hypercalcaemia associated with raised parathormone . an attempt of steroids for treatment of occult disease was unsuccessful. Her past medical record showed that since childhood she had had painful and swollen heels, especially after stress. Physical findings showing mild heart condition "> mitral valve stenosis and regurgitation and mild aortic regurgitation suggested a possible diagnosis of rheumatic heart disease.

On this admission the patient complained of fever and night sweats. She was in good general condition with mildly raised vital sign . Physical examination was unremarkable apart from a 2/6 heart murmur compatible with mitral regurgitation and mild lymphadenopathy. The patient repeated an entire examination for her fever of unknown origin, including serological tests and cultures, liver biopsy, cerebral artery biopsy, bone marrow biopsy, lymph gland biopsy, bronchoscopy, abdominal arteriography, and a number of other imaging studies. No major pathological finding was evident apart from anaemia (haemoglobin 86 g/l) and a raised erythrocyte erythrocyte sedimentation rate (90 mm/1st h). The attacks of fever were controlled with daily administration of 60 mg prednisone.

At now we learnt that her brother had FMF, which was successfully treated with colchicine. Although the clinical picture of the patient wasn't implicational FMF, we performed a molecular analysis of her DNA trying to find mutations within the MEFV gene. The results showed that the patient was homozygous for the M694V mutation. FMF was diagnosed and colchicine treatment started. The patient took colchicine for about two months, but couldn't tolerate it. 

PATIENT B

A 54 year old Arab woman, born within the Lebanon, was mentioned our department with coronary failure of no apparent cause. She had been previously admitted to a different hospital at the age of 32 years due to splenomegaly and proteinuria. Bone and liver biopsies were administered , but the results were unavailable. Three years later a kidney biopsy was performed and showed focal glomerulonephritis with sclerosis. Since the age of 37 the patient had been readmitted repeatedly due to attacks of fever, cough, and weakness. Therapeutic trials with antibiotics for tract infection were partially effective. computerized tomography of the chest disclosed localised bronchiectasis within the left lower lobe of the lung. However, a gallium scan didn't show any pathological emission. At the age of 40 treatment with steroids was started due to a coffee level of antinuclear think about the serum and suspicion of an underlying collagen vascular disease. The trial was unsuccessful and therefore the fever attacks continued.

Re-evaluation of the patient's condition at the age of fifty showed several new findings, including symptoms and signs of left coronary failure and therefore the appearance of left bundle branch block within the electrocardiogram. Kidney, duodenal, and rectal biopsies showed sedimentation of amyloid fibrils round the blood vessels. An echocardiography performed during this admission disclosed a mildly dilated ventricle with global hypokinesis with regional variation (severe hypokinesis of septum and mild hypokinesis of the posterolateral wall); mildly to moderately reduced left ventricular function (left ventricular ejection fraction was 40–50% with no signs of a restrictive pattern); and wall thickness within the upper limits of normal. Cardiac catheterisation showed patent coronary arteries, moderately enlarged, and severely reduced contraction of the ventricle . Repeated bacterial cultures (also for mycobacterium), and serological tests for infection or non-infectious inflammation, were normal or sterile, respectively. A myocardial biopsy showed deposition of amyloid A surrounding individual myocytes (fig 1). A diagnosis of chronic bronchiectasis with secondary amyloidosis was proposed. However, the ethnic origin of the patient, her clinical history of fever, and therefore the finding of amyloidosis, raised the likelihood of FMF. Indeed, molecular analysis showed that the patient was homozygous for the M694V mutation at the MEFV gene. Treatment with colchicine was started and therefore the refore the response was dramatic: the febrile attacks disappeared and the patient features a continuous feeling of wellbeing that she has not had for several years.

Discussion

Petersdorf and Beeson defined fever of unknown origin in 1961 as (a) temperatures above 38.3°C on several occasions; (b) duration of fever of quite three weeks; and (c) failure to succeed in a diagnosis despite one week of inpatient investigation.6

FMF may be a disease during which fever is that the main manifestation. However, the periodic nature of the disease during which the fever lasts up to 96 hours, and therefore the relatively long interval between the attacks, are major criteria which assist in making the diagnosis of FMF. Furthermore, in contrast with most of the cases of fever of unknown origin, patients with FMF look completely healthy between the attacks. Therefore, the diagnosis of FMF is comparatively easy in patients with typical clinical manifestations, case history , and appropriate ethnic origin. For that reason, during a large series of patients with fever of unknown origin, especially in those with a protracted course of fever, only a couple of had a diagnosis of FMF.7 ,8 As this diagnosis was made on clinical grounds only, it's still possible that even in these few cases the diagnosis wasn't correct. The recent isolation of germline mutations of the 55 kDa tumour necrosis factor receptor causing a family of dominantly inherited autoinflammatory syndromes further emphasises the doubts and difficulties in clinical diagnosis of periodic fevers.9 Thus the relatively new diagnostic tool, molecular analysis, helps in making a definitive diagnosis of FMF in questionable or atypical cases.

The patients described herein both have appropriate ethnic origins as FMF is prevalent among North African Jews also as among Arabs.1 ,2 However, their clinical presentations were unusual. the primary patient had prolonged fever instead of periodic attacks. She didn't complain of typical serositis. She had night sweats and lymphadenopathy, that lymphoma was thoroughly searched. She was admitted to 2 hospitals and had undergone extensive clinical and laboratory investigations to exclude infection, malignancy, or collagen vascular disease, with none success. Because her brother was diagnosed as having FMF the patient underwent a molecular analysis. The test for detecting mutations liable for FMF showed that she was homozygous for the M694V mutation. the shortage of knowledge about her response to colchicine thanks to her intolerance to the present drug may raise some doubt about the diagnosis of FMF. However, the mixture of molecular findings of homozygosity for the M694V mutation and therefore the episodes of fever strongly indicate a diagnosis of FMF.

The second patient was transferred to our department for investigation of dilated cardiomyopathy. She had myocardial amyloidosis not usually seen in secondary amyloidosis that was thought to be secondary to bronchiectasis during a minor segment of her left lower lobe. However, molecular analysis disclosed that she was also homozygous for the M694V mutation. The question one may ask is whether or not this patient had quite one disease? We believe that this wasn't the case as, on reflection , most of her complaints and findings could fit the diagnosis FMF, and she or he responded extremely well to colchicine treatment, though she had no case history of FMF. it's known that type II FMF phenotype presents with amyloidosis without preceding typical FMF attacks. The presence of amyloid in her myocardium is rare and doubtless reflects a disease course of the many years with atypical presentation (dilated cardiomyopathy with no restrictive pattern). Such a pattern has not been reported before in FMF and isn't a standard consequence of bronchiectasis.10

Several studies comparing phenotype manifestations and genotype analysis have disclosed that patients with FMF homozygous for the M694V mutation have a more severe disease manifested by early onset, more frequent attacks, joint disease, and need higher doses of colchicine.11-13 Moreover, such patients are more susceptible to develop amyloidosis.13 ,14 quite 18 mutations of the MEFV gene are known, and studies have shown that some have low penetrance (E148Q, P396S), whereas others cause a milder disease (V726A).13 ,15 a couple of studies didn't find similar results.16 Our experience is in unison with the previous studies and that we believe that the presence of the M694V mutation on both alleles in our patients strongly confirms the diagnosis of FMF.

We describe herein two unusual cases of fever of unknown origin thanks to FMF. Cases like these can mimic the presentation of other medical conditions, like lymphoma, collagen vascular diseases, or infectious diseases. The presence of a protracted benign course amid amyloidosis, kidney failure , and coronary failure , should raise suspicions of FMF, especially within the absence of other causes of fever. the power conclusively to diagnose or exclude FMF by an easy and reliable laboratory examination (that is, molecular analysis) changes the way we regard FMF. Nowadays, FMF shouldn't be considered as a diagnosis of exclusion.

Nevertheless, we must still twiddling my thumbs and careful in using molecular analysis for diagnosis of FMF , especially in asymptomatic subjects because the complex issue of a genotype/phenotype relation has not yet been settled.

We believe that, although rare, FMF should be included within the medical diagnosis of patients with fever of unknown origin, and molecular analysis for FMF should be complementary to their examination at some point. This treatable disease shouldn't be left undiagnosed as missing the diagnosis can have severe consequences. Special efforts should be made to diagnose FMF, particularly when the ethnic background is acceptable .