Neonatal onset familial Mediterranean fever

Abstract

Objectives: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent, self-limited attacks of fever with serositis. Recently, it was shown that FMF patients with early disease onset have more severe disease. The aim of this study was to describe the demographic, clinical and genetic features of FMF patients who had disease onset during the neonatal period.

Methods: Medical records of all patients diagnosed as FMF and had been seen in the outpatient clinic of Paediatric Rheumatology department between January 2013 and January 2014 were retrospectively evaluated. Patients with disease onset during the first month of life were included to the study.

Results: Among 317 patients; 19 (12 males) were included to the study. Approximately 60% of the patients had family history of FMF. Homozygous p.M694V mutation was detected in 42% of the cases. Thirteen patients present with attacks of fever and remaining had attacks in the form of restlessness, resembling infantile colic starting in the neonatal period. Majority of these patients developed classical abdominal attacks between the ages of 1 and 2.5 years. The diagnosis of FMF was significantly delayed; the median age at onset of therapy was 3.5 years (range 7 months–17 years).

Conclusion: Patients with FMF could have complaints even in the neonatal period. Homozygous p.M694V mutation is a prominent mutation in this group of patients. In order to prevent diagnostic delay physicians dealing with these type of patients should be more vigilant.     

Familial Mediterranean fever gene mutations in the Southeastern region of Turkey and their phenotypical features

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent inflammatory attacks of serosal membranes. Several studies have focused on the differences between frequency of the mutations and their phenotypical manifestations. The aim of this study was to evaluate whether or not this phenotypical variation is associated with the existence of particular mutations. Twelve MEFV (Mediterranean fever) gene mutations were investigated in 119 patients suffering from FMF. Heterozygote M694V (21/119), heterozygote E148Q (21/119), homozygote M694V (17/119) and heterozygote V726A (12/119) mutations were the most common mutations. Patients were grouped according to the presence of the M694V mutation: group I was M694V/M694V, group II was M694V/others, and group III was other/other. Mean severity scores for the groups were 13.94 ± 4.10, 10.79 ± 3.01 and 8.31 ± 2.26, respectively. There were statistically significant differences between the mean severity scores of groups I and II (p = 0.029), groups I and III (p < 0.0001), and groups II and III (p < 0.0001). Diagnosis of amyloidosis was established in four (23%) patients of group I, and three (8%) patients of group II, but in none of the patients in group III. There was also a statistically significant difference between groups I and III (p = 0.046), but not between groups II and III (p = 0.083) and groups I and II (p = 0.317) in terms of amyloidosis development. In conclusion, we found a higher disease severity score and higher prevalence of amyloidosis in FMF patients who were M694V mutation carriers. Many ethnic groups live in Anatolia and more ethnic origin-based studies are needed to determine the real effect of these mutations on disease severity and amyloidosis.     

Microarray analysis of circulating microRNAs in familial Mediterranean fever

Objectives: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in MEFV. Mutations in exon 10 are associated with typical FMF phenotypes, whereas the pathogenic role of variants in exons 2 and 3 remains uncertain. Recent evidence suggests that circulating microRNAs (miRNAs) are potentially useful biomarkers in several diseases. Therefore, their expression was assessed in FMF.

Methods: The subjects were 24 patients with FMF who were between attacks: eight with exon 10 mutations (group A), eight with exon 3 mutations (group B), and eight without exon 3 or 10 mutations (group C). We also investigated eight cases of PFAPA as disease controls. Exosome-rich fractionated RNA was subjected to miRNA profiling by microarray.

Results: Using the expression patterns of 26 miRNAs, we classified FMF (groups A, B, and C) and PFAPA with 78.1% accuracy. In FMF patients, groups A and B, A and C, and B and C were distinguished with 93.8, 87.5, and 100% accuracy using 24, 30, and 25 miRNA expression patterns, respectively.

Conclusions: These findings suggest that expression patterns of circulating miRNAs differ among FMF subgroups based on MEFV mutations between FMF episodes. These patterns may serve as a useful biomarker for detecting subgroups of FMF.     

Fatigue in pediatric patients with familial Mediterranean fever

Abstract

Objectives: Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited attacks of fever with serositis involving the peritoneum, pleura and joints. Fatigue is a common problem in many pediatric rheumatic diseases; however, has not been evaluated systematically in FMF patients. Accordingly, the aim of this study was to evaluate fatigue and its possible allied factors in patients with FMF.

Methods: Patients with FMF, aged between 10 and 21 years, were assessed by completed validated fatigue questionnaire (Checklist Individual Strength-20). As a control group, patients with chronic rheumatic diseases and healthy children without any chronic disease were included.

Results: The study group comprised 111 patients with FMF, 54 with other chronic rheumatic diseases and 79 healthy subjects. While the CIS-20 total score and subscale scores (including subjective experience of fatigue) were similar between patients with FMF and those with other chronic rheumatic diseases (p?>?.05); both groups had significantly higher scores when compared with healthy subjects (p?<?.05). FMF patients with musculoskeletal complaints had significantly higher scores of subjective experiences of fatigue when compared to those without those complaints.

Conclusions: Fatigue is a common but unrecognized complaint in patients with FMF. Familial Mediterranean fever seems to be a chronic disease with inter attack ongoing complaints.     

The frequency of the celiac disease among children with familial Mediterranean fever

We aimed to assess the frequency of celiac disease (CD) in patients with Familial Mediterranean Fever (FMF). This prospective study was carried out from October 2015 to March 2016 and included 303 patients with FMF. We used 98 sex- and age-matched healthy subjects as a control group. Levels of total IgA and tissue transglutaminase (tTG) IgA antibody were measured in all groups. Those with increased level of tTG IgA were tested for anti-endomysium IgA antibodies (EMA). Patients with positive EMA underwent gastro-duodenoscopy and intestinal biopsy for a definite diagnosis of CD. Only 9 of 303 patients (2.9%) were positive for tTG IgA. Patients positive for tTG IgA were then tested for EMA and only one of them (0.3%) had a positive result. This patient underwent gastro-duodenoscopy. The pathological report was compatible with Marsh 0 classification score for the diagnosis of CD. Two subjects from the control group were positive for tTG IgA but none of them had positive EMA antibodies. We did not find CD in the large cohort of childhood FMF patients. The prevalence of CD did not show association with presence of childhood FMF in this study and CD would not be a considerable complication of childhood FMF.     

MEFV mutations in Tunisian patients suffering from familial Mediterranean fever

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations in Tunisian patients. PATIENTS AND METHODS: This study was performed in the Genetic Department of Tunis University Hospital. A clinical diagnosis of FMF was made according to published criteria. Mutation screening of the MEFV gene was performed in the Human Genetic Laboratory of the "Faculté de Medecine de Tunis" for 8 mutations including the 5 most common known mutations M694V, V726A, M694l, M680l, and E148Q. The tests performed were polymerase chain reaction (PCR) restriction-digestion for M694V, V726A, M680l, R761H, E148Q; amplification refractory mutation system for A744S, M694l; and PCR-electrophoresis assay for l692del. RESULTS: Of the 139 unrelated patients investigated, 61 (44%) had 1 or 2 mutations. In 78 (56%) probands no mutation was identified: 28 patients were homozygous; 16 were compound-heterozygous; 2 had complex alleles; and 17 had only 1 identifiable mutation. Of the mutations, M680l, M694V, M694l, V726A, A744S, R761H, l692DEL, and E148Q accounted for 32, 27, 13, 5, 3, 1, 1, and 18%, respectively. CONCLUSION: The profile of the MEFV gene mutations in the Tunisian population is concordant with other Arab populations but with some differences. M680l is the most common mutation, while V726A, the commonest mutation among Arabs, is rare in our population.     

Evaluation of disease severity in familial Mediterranean fever

OBJECTIVE: To establish a new, objective, statistically based severity score for familial Mediterranean fever (FMF). METHODS: One hundred consecutive FMF patients were evaluated independently by 2 FMF experts for severity of their disease and were assigned to 1 of 3 severity levels: mild, intermediate, or severe. Nine candidate criteria, reflecting objective suffering and disability, were analyzed to determine their weight for patient placement in the 3 predefined severity groups. RESULTS: Candidate criteria best differentiating between the 3 patient categories were the frequency of attacks, the number of sites affected during an attack and during the course of the disease, and the duration of the attacks. These criteria were applied in a classification-tree model to establish a new FMF-severity score (F-SS). The first set of F-SS (F-SS-1) was highly sensitive and specific. Integrating F-SS-1 with clinical parameters strongly associated with disease severity resulted in a simplified score, the second set of F-SS (F-SS-2). CONCLUSIONS: New, useful, objective, and valid severity scores were established and found to distinguish between patients with mild, intermediate, and severe diseases with high sensitivity and specificity. RELEVANCE: The F-SS established may be important for treatment decisions, prognosis evaluation, and comparative analysis of patient populations.     

Egyptian tale from India: application of whole‐exome sequencing in diagnosis of atypical familial Mediterranean fever

Clinical diagnosis of autoinflammatory diseases requires a high degree of clinical suspicion and clinching molecular evidence to substantiate the diagnosis. This is more so in populations with low prevalence of these disorders. In this report, we describe the case of a young man from India with recurrent fever and persistent arthritis. The patient's forefathers were of Egyptian ancestry who practiced consanguinity. Molecular genetic analysis using whole‐exome sequencing suggested the presence of variants c.443A>T:p.E148V and c.442G>C:p.E148Q in the MEFV gene, earlier independently shown to be associated with familial Mediterranean fever (FMF) in a compound heterozygous state. The variants were further confirmed by capillary sequencing. This report also highlights the application of whole exome sequencing to delineate the allelic differences in the variants apart from serving as a quick genetic screening approach for autoinflammatory diseases. To the best of our knowledge, this is the first report of a compound heterozygosity for the two well‐characterized variants associated with atypical FMF in a patient.     

Vasculitis in siblings with familial Mediterranean fever: a report of three cases and review of the literature

Familial Mediterranean Fever (FMF) is characterized by recurrent attacks of self-limited polyserositis and fever. Several types of vasculitis are associated with FMF: polyarteritis nodosa, Henoch–Schonlein purpura (HSP), and protracted febrile myalgia (PFM). We describe three cases of vasculitis in four siblings of a Sephardic Jewish family with FMF and reviewed the literature. One brother and one sister developed severe HSP with intestinal involvement while another brother developed PFM. Genetic tests in three brothers confirmed the M694V mutation on both alleles. Vasculitides may be a clinical feature of FMF with a higher familiar prevalence. MEFV mutations may act as a genetic susceptibility factor for vasculitides in FMF patients.     

Encapsulating peritonitis and familial Mediterranean fever

AIM: To investigate the relationship between encapsulating peritonitis and familial Mediterranean fever (FMF). METHODS: The patient had a history of type 2 diabetes and Iaparoscopic cholecystectomy was performed one year ago for cholelithiasis. Eleven months after the operation she developed massive ascites. Biochemical evaluation revealed hyperglycemia, mild Fe deficiency anemia, hypoalbuminemia and a CA-125 level of 2 700 IU. Ascitic evaluation showed characteristics of exudation with a cell count of 580/mm~3. Abdominal CT showed omental thickening and massive ascites. At exploratory laparotomy there was generalized thickening of the peritoneum and a Iaparoscopic clip encapsulated by fibrous tissue was found adherent to the uterus. Biopsies were negative for malignancy and a prophilactic total abdominal hysterectomy and bilateral salpingooophorectomy were performed. RESULTS: The histopathological evaluation was compatible with chronic nonspecific findings and mild mesothelial proliferation and chronic inflammation at the uterine serosa and liver biopsy showed inactive cirrhosis. CONCLUSION: The patient was evaluated as sclerosing encapsulating peritonitis induced by the iaparoscopic clip acting as a foreign body. Due to the fact that the patient had FMF the immune response was probably exaggerated.     

Protracted familial Mediterranean fever arthritis

Familial Mediterranean fever (FMF) is an inherited disorder characterized by recurrent attacks of fever and abdominal, chest, and articular pain. The articular attack of FMF is typically an acute, self-limited, large joint monoarthritis most often affecting the knee or hip. Rarely, a more protracted arthritis may occur. We describe two unusual cases of long-standing FMF arthritis with excellent response to synovectomy. Received: 26 March 1999 / Accepted: 29 July 1999     

Abdominal CT findings in nephropathic amyloidosis of familial Mediterranean fever

To evaluate the abdominal CT features of reactive amyloidosis, abdominal CT scans of 20patients with amyloidosis of familial Mediterranean fever (FMF) were reviewed and compared with abdominal CT scans of2 control groups: 22 patients with chronic renal failure (CRF) due to non-amyloidotic kidney diseases and 40 patients with normal kidney function. The kidney size of patients with amyloidosis of FMF were found to vary during the course of the disease from normal or slightly larger than normal at the proteinuric phase, to smaller than normal and comparable to kidney size in CRF, at the uremic stage. Compared to kidney disease of other causes, more patients with FMF-amyloidosis had dense kidneys with coarse parenchymal calcification and calcification in other abdominal organs. Patients with FMF-amyloidosis had fewer aortic calcifications than patients with non-amyloidotic kidney disease. These findings suggest that kidney disease of reactive amyloidosis may have abdominal CT findings distinguishing it from other types of kidney diseases.