Erysipelas-like erythema as the presenting feature of familial Mediterranean fever.

BACKGROUND: 'Erysipelas-like' erythema (ELE) is a well recognized, although uncommon, manifestation of familial Mediterranean fever (FMF), which is frequently mistaken for infectious erysipelas, especially when forming the initial disease presentation. AIM: To clinically and genetically characterize ELE as the first manifestation of FMF. METHODS: FMF patients with ELE as the first disease presentation (study group), were compared with FMF patients with ELE, appearing during the disease course (control group I), and to those FMF patients who never had ELE (control group II). RESULTS: Patients of the study group were comparable to patients without ELE with respect to all demographic, clinical and genetic features studied, and yet differed from patients with ELE appearing later in the disease course in disease severity score (1.7 ± 0.4 vs. 2.4 ± 0.6, P = 0.01), length of diagnosis delay (7.2 ± 6.4 vs. 2.3 ± 3.3 years, P=0.037), age of FMF onset (24.8 ± 19.9 vs. 5.6 ± 5.7 years of age, P=0.014) and rate of homozygosity to the M694V mutation (14.3% vs. 68.7% respectively). ELE traits in the study and control groups were alike. CONCLUSIONS: FMF with ELE as the first disease manifestation form an uncommon subgroup, clinically and genetically diverging from the rest of the FMF-ELE patients.

Systemic lupus erythematosus and familial Mediterranean fever: a possible negative association between the two disease entities--report of four cases and review of the literature.

Serositis is a common clinical manifestation of systemic lupus erythematosus (SLE), as well as being the hallmark of familial Mediterranean fever (FMF), the most prevalent monogenic disease in the Jewish population. We have treated four patients who suffered from both SLE and FMF since 2001 in our clinic, which also serves as the national center for FMF. Our cases illustrate both similarities and dissimilarities between the clinical manifestations of these two diseases, an aspect which should be borne in mind, especially in the young female patients. In general, it seems that co-occurrence of FMF moderates the presentation of lupus.

Diagnosis delay in familial Mediterranean fever (FMF): social and gender gaps disclosed.

OBJECTIVE: To characterize the factors contributing to a greater than 10 year delay in the diagnosis of familial Mediterranean fever (FMF). METHODS: 50 patients, in whom diagnosis of FMF was delayed by more than 10 years, comprised the study population. The clinical, demographic and molecular genetic characteristics were compared to a control group of 50 FMF patients, in whom the diagnosis was made within a reasonable time period (less than 5 years from onset). Additional factors contributing to a delayed diagnosis in the study group, including physician-related factors, patient-related factors, disease-factors and other factors, were studied as well. RESULTS: Overall, attack sites, duration and severity were comparable among study and control groups. No differences in ethnic origin or family history of FMF were noted between the groups. There were significantly more females (p = 0.009), newly-arrived immigrants (p = 0.005) and carriers of unidentified MEFV mutations (p = 0.04) in the study group. Delayed diagnosis of FMF stemmed from misdiagnosis and physician negligence (70%), as well as from patient negligence (70%). The diagnosis was ultimately made mainly due to a change in disease pattern and other causes, such as diagnosis of FMF in a relative. CONCLUSION: The study unveils unexpected causes behind a prolonged delay in the diagnosis of FMF such as social status (immigrant), female gender, physician negligence and lack of patient awareness. The possibility that the delay stems from a milder disease pattern was dismissed.

A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD).

Although familial Mediterranean fever (FMF) is an autosomal recessive disorder, preliminary partial mutation analysis suggested that about 60% of FMF patients, who also suffer from Behçet's disease (FMF-BD), have only a single mutated FMF gene (MEFV). In this study, the possibility that patients with FMF-BD may indeed be carriers of a single mutated MEFV is further analysed. The presence of mutations in the coding region of MEFV of eight patients with FMF-BD, representing six families with 47 members, was determined by sequencing. A possible role for the non-carrier chromosome and for BD in the expression of FMF in patients with a single mutated MEFV allele was determined by analysing the association between these variables and the presence of FMF in heterozygous kin. Sequence analysis revealed that all eight patients had indeed only one mutation in the coding region of MEFV. The patients' non-carrier chromosomes converged into three different MEFV haplotypes and were shared by heterozygous unaffected kin in five of six families. BD was found in 10 of 11 carriers with FMF vs one of 16 carriers without FMF (P < 0.001). These results suggest that FMF may be expressed in individuals harbouring only one coding mutation in MEFV. The findings argue against a role for the non-carrier chromosome in the induction of FMF, and suggest that the FMF phenotype in this cohort was associated with the simultaneous presence of BD. These findings may mirror a more generalised rule, that FMF may be precipitated in carriers of a single mutated FMF gene by factors unrelated to the other MEFV allele.

Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever.

OBJECTIVE: To study genotype-phenotype correlation for the 4 most common genotypes found among patients with familial Mediterranean fever (FMF). METHODS: Thirty patients with the M694V/M694V genotype, 32 with M694V/V726A genotype, 25 with M694V/E 148Q genotype, and 21 with V726A/V726A genotype were assessed for various clinical manifestations of FMF, and overall disease severity. RESULTS: Patients with the M694V/M694V genotype were found to have an earlier age of onset, higher frequency of joint involvement, higher frequency of erysipelas-like erythema, and required higher doses of colchicine to control the disease compared to the other 3 genotypes. CONCLUSION: The M694V/M694V genotype is associated with more severe disease compared to other common genotypes in patients with FMF.

Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics.

To determine the prevalence and characterize demographic, clinical, and genetic features of familial Mediterranean fever (FMF) of late onset, all patients experiencing their first FMF attack at age 40 years or more were identified using the computerized registry of our FMF clinic, and then thoroughly interviewed and examined. The control group consisted of 40 consecutive FMF patients, who arrived at the FMF clinic for their regular follow-up visit and were 40 years of age or older at the time of the examination. The severity of the disease in patients and controls was determined using a modified score, developed previously. Mutational analysis in the FMF gene was performed using a commercial kit. Only 20 of 4000 (0.5%) patients had late-onset FMF. These patients were mostly men, of non-North African origin, P < 0.05 compared to controls. All had abdominal attacks and in most these were the only manifestation of their disease, P < 0.001. None had chronic or prolonged manifestations of FMF, for example, amyloidosis, chronic arthritis, or protracted myalgia, P < 0.001. The response to treatment was good despite using low colchicine dose, P < 0.05. The overall severity score indicated a mild disease, P < 0.001. Mutational analysis revealed absence of M694V homozygosity, P < 0.01, compared to our regular FMF population. We conclude that the onset of FMF in a late age defines a milder form of disease with typical clinical, demographic, and molecular genetic characteristics.

MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a major cause of AA amyloidosis. Recently, the gene (MEFV) causing this disease was cloned and 16 disease associated mutations have been described. We have analyzed 178 FMF patients, 30 of whom also suffered from amyloidosis, for 4 mutations in MEFV. Mutations were identified in 29 of the FMF amyloidosis patients. 27 FMF amyloidosis patients were homozygous for M694V. One patient was found to be homozygous for both V726A and E148Q. In another patient E148Q and V726A were found on one allele, while V726A was found on the second allele. Amyloidosis was far more common among patients homozygous for M694V compared to patients with other mutations (P < 0.0001). In 3 patients homozygous for M694V, amyloidosis was the sole manifestation of the disease.

Construction of an approximately 700-kb transcript map around the familial Mediterranean fever locus on human chromosome 16p13.3.

We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of genomic DNA around D16S3370, a marker showing a high degree of linkage disequilibrium with FMF, was sequenced to completion, and the sequence annotated. A transcript map reflecting the minimal number of genes encoded within the approximately 700 kb of genomic DNA surrounding the FMF locus was assembled. This map consists of 27 genes with discreet messages detectable on Northerns, in addition to three olfactory-receptor genes, a cluster of 18 tRNA genes, and two putative transcriptional units that have typical intron-exon splice junctions yet do not detect messages on Northerns. Four of the transcripts are identical to genes described previously, seven have been independently identified by the French FMF Consortium, and the others are novel. Six related zinc-finger genes, a cluster of tRNAs, and three olfactory receptors account for the majority of transcribed sequences isolated from a 315-kb FMF central region (between D16S468/D16S3070 and cosmid 377A12). Interspersed among them are several genes that may be important in inflammation. This transcript map not only has permitted the identification of the FMF gene (MEFV), but also has provided us an opportunity to probe the structural and functional features of this region of chromosome 16.

Calcification in untreated non-Hodgkin's mediastinal lymphoma.

We report a case of calcifications in mediastinal non-Hodgkin's lymphoma. Although calcification may occur in lymphoma after chemotherapy or radiotherapy in areas of fibrous healing and scar formation, it has been reported only rarely in untreated non-Hodgkin's lymphoma.

A high-resolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups.

Familial Mediterranean fever (FMF) is a recessive disorder of inflammation caused by mutations in a gene (designated MEFV) on chromosome 16p13.3. We have recently constructed a 1-Mb cosmid contig that includes the FMF critical region. Here we show genotype data for 12 markers from our physical map, including 5 newly identified microsatellites, in FMF families. Intrafamilial recombinations placed MEFV in the approximately 285 kb between D16S468/D16S3070 and D16S3376. We observed significant linkage disequilibrium in the North African Jewish population, and historical recombinants in the founder haplotype placed MEFV between D16S3082 and D16S3373 (approximately 200 kb). In smaller panels of Iraqi Jewish, Arab, and Armenian families, there were significant allelic associations only for D16S3370 and D16S2617 among the Armenians. A sizable minority of Iraqi Jewish and Armenian carrier chromosomes appeared to be derived from the North African Jewish ancestral haplotype. We observed a unique FMF haplotype common to Iraqi Jews, Arabs, and Armenians and two other haplotypes restricted to either the Iraqi Jewish or the Armenian population. These data support the view that a few major mutations account for a large percentage of the cases of FMF and suggest that some of these mutations arose before the affected Middle Eastern populations diverged from one another.

Criteria for the diagnosis of familial Mediterranean fever.

OBJECTIVE: To establish a new set of criteria for the diagnosis of familial Mediterranean fever (FMF). METHODS: Twenty-seven features and manifestations typical of FMF were studied to determine their prevalence in 105 patients with FMF and 106 controls. Diagnosis of FMF in the study group was based on clinical judgment. Controls were patients with a variety of other diseases who presented to the emergency room or outpatient clinics with recurrent episodes of pain in body sites usually involved in FMF attacks. Manifestations observed to be significantly more common in FMF patients than in controls were incorporated into the rule proposed for diagnosis of FMF, based on a model of major, minor, and supportive criteria. RESULTS: Two sets of diagnostic criteria were established. A conservative criteria set for diagnosis of FMF was based on the presence of 1 major or 2 minor criteria, or 1 minor plus 5 supportive criteria, and a simple criteria set for diagnosis of FMF required 1 major or 2 minor criteria. The sensitivity and specificity of these 2 criteria sets were >95% and >97%, respectively. CONCLUSION: The proposed new sets of criteria were highly sensitive and specific, and could be used to readily diagnose FMF and to distinguish FMF from other periodic febrile diseases.

Quality of life of patients with familial Mediterranean fever.

OBJECTIVE: The aim of the present study was to assess the quality of life (QOL) of patients with Familial Mediterranean Fever (FMF) and to explore its possible contributing factors. METHODS: One hundred and two FMF patients were evaluated using a QOL Scale, and were compared to 124 healthy controls. The QOL scale includes 16 items, each measured on a 7-point scale (7 indicating maximal satisfaction). RESULTS: The total QOL score of FMF patients was significantly lower than that of the controls: 81.6 +/- 19.2 vs 88.0 +/- 12.8 (p < 0.01). Male and female patients reported similar QOL scores. QOL was inversely correlated with the number of FMF attacks in the last year (r = -0.302, p = 0.002), and with the number of FMF hospitalizations (r = -0.238, p = 0.017). Patients with widespread pain, sleep disturbances and headaches had significantly lower QOL scores than patients without them. CONCLUSIONS: The QOL of FMF patients was found to be impaired compared to healthy controls. Further studies are needed to determine the exact factors affecting the quality of life of FMF patients.

Construction of a 1-Mb restriction-mapped cosmid contig containing the candidate region for the familial Mediterranean fever locus (MEFV) on chromosome 16p 13.3.

In this paper we describe the assembly and restriction map of a 1.05-Mb cosmid contig spanning the candidate region for familial Mediterranean fever (FMF), a recessively inherited disorder of inflammation localized to 16p13.3. Using a combination of cosmid walking and screening for P1, PAC, BAC, and YAC clones, we have generated a contig of genomic clones spanning approximately 1050 kb that contains the FMF critical region. The map consists of 179 cosmid, 15 P1, 10 PAC, 3 BAC, and 17 YAC clones, anchored by 27 STS markers. Eight additional STSs have been developed from the approximately 700 kb immediately centromeric to this genomic region. Five of the 35 STSs are microsatellites that have not been previously reported. NotI and EcoRI mapping of the overlapping cosmids, hybridization of restriction fragments from cosmids to one another, and STS analyses have been used to validate the assembly of the contig. Our contig totally subsumes the 250-kb interval recently reported, by founder haplotype analysis, to contain the FMF gene. Thus, our high-resolution clone map provides an ideal resource for transcriptional mapping toward the eventual identification of this disease gene.

Increased prevalence of joint manifestations in patients with recurrent aphthous stomatitis (RAS)

OBJECTIVE: To characterize the systemic manifestations and joint disease in patents with recurrent aphthous stomatitis (RAS). METHODS: The presence and features of extra-oral manifestations were determined by a rheumatologist, who examined and interviewed 64 patients, referred during 1993 to the oral medicine clinic for treatment of RAS. Controls were 65 medical staff members of a military clinic associated with the hospital. RESULTS: Based on the rheumatologist's findings and published criteria, the patients were diagnosed as suffering from RAS alone (24 patients), Reiter's syndrome (8), Behçet disease (8), familial Mediterranean fever (1), or RAS with undiagnosable extra oral manifestations (23). Thirteen patients in the last group had joint disease (p < 0.01 compared to the controls), characterized by recurrent mono- or oligoarthritis/arthralgia of short duration, affecting mostly the large joints. Conjunctivitis, pustular rash, lower back pain and urethritis/cervicitis were also common in RAS patients, but only the latter was significantly more frequent in RAS patients than in controls (p < 0.02). CONCLUSION: These findings suggest that patients with RAS have an increased frequency of a palindromic type joint disease.

Musculoskeletal manifestations of brucellosis: a study of 90 cases in Israel.

Rheumatological manifestations are frequently reported in patients with brucellosis. In a retrospective study of 90 patients diagnosed with brucellosis over a period of 18 years, 83 (92%) patients were Bedouins, 55 of whom (61%) reported ingestion of unpasteurized goat milk and goat milk products. The male/female ratio was 1:1, and the adult to child ratio was 3:2. The mean age of the patients was 25 years (range, 1-72 years). Rheumatological manifestations (myalgia, arthralgia, and arthritis) were reported in more than half of the patients. These manifestations started on days 3 and 4 of the disease and were mild to moderate in severity. Myalagia was evident in 49 (54%) patients and was more common in adults than in children (67% versus 37%; P < .01) and in men (67%) than in women (42%; P < .01). Arthralgia was the most common musculoskeletal manifestation, found in 55 (61%) patients, and occurred more often in children than in adults (74% versus 52%; P < .05). Arthritis was detected in 37 (41%) patients. The hip and knee joints were the most common sites of arthritis (31% each) followed by sacroiliac involvement (17%) and shoulder or spine involvement (5% each). Arthritis was also more common in children (63% versus 29%; P < .01). The prevalence of arthritis was similar in men and women. Cure was achieved in all patients after antibiotic therapy.

Fibromyalgia in familial Mediterranean fever.

OBJECTIVE: To determine whether chronic lower body pain in a subpopulation of patients with familial Mediterranean fever (FMF) is due directly to the musculoskeletal manifestations of FMF or whether they are connected to mechanical problems in the low back and leg/foot or to other factors operative in fibromyalgia (FM). METHODS: In 93 consecutive patients with FMF a point count of 14 tender points (TP) was conducted by thumb palpation. Tenderness thresholds were assessed in some of the TP and of control point sites by Chatillon dolorimeter. RESULTS: In female patients with FMF dolorimeter thresholds of fibrositic and control point sites were significantly lower than in male patients with FMF (p < 0.004). Also patients with FMF with back pain and foot/leg pain are more tender than patients with FMF without this characteristic (p < 0.001). CONCLUSION: The detection of FM and definition of tenderness thresholds is relevant to this disease, since musculoskeletal complaints are common in this group of patients but not always explained by objective findings.