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1.
Harefuah ; 158(9): 576-578, 2019 Sep.
Artigo em Hebraico | MEDLINE | ID: mdl-31507107

RESUMO

INTRODUCTION: Gout is an inflammatory condition mediated by Interleukin-1-beta (IL-1ß). A mutation in the MEFV gene (the gene related to Familial Mediterranian fever) may cause an elevation in IL-1ß, and is associated with a variety of inflammatory conditions. Reports in the literature are inconsistent as to whether a mutated MEFV gene is related to the phenotype of gout. OBJECTIVES: To assess whether a carriage state of a mutation in the MEFV gene correlates with the expression and severity of gout. METHODS: A total of 73 patients, 50 with gout and 23 with hyperuricemia were examined for an MEFV mutation. Carriage rate was compared between hyperuricemic and gout patients, and disease activity measures were compared between MEFV mutation carriers and non-carriers. RESULTS: We did not find a statistically significant difference in the carriage rate of an MEFV mutation between gout patients and hyperuricemic patients without gout, nor did we find a correlation between MEFV mutation carriage and gout severity. CONCLUSIONS: Further large-scale studies should be conducted in order to determine a possible correlation between MEFV mutation carriage and gout.


Assuntos
Gota/genética , Pirina/genética , Proteínas do Citoesqueleto , Humanos , Mutação
2.
Intern Med ; 58(14): 2025-2028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308342

RESUMO

A 37-year-old man developed abdominal pain and the frequency of severe abdominal pain steadily increased to once a month. He was therefore admitted to our hospital. Abdominal CT showed bowel obstruction. It revealed transient stenosis in the small intestine. There were no symptoms such as fever or weight loss, it seemed unlikely that the patient had inflammatory bowel disease. Considering the history of recurrent abdominal pain, Familial Mediterranean Fever (FMF) was considered. As a result, a genetic analysis revealed mutations in exons 3 and 8 of the MEFV gene. We herein report the first known case of FMF with transient small bowel stenosis in Japan.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Pirina/genética , Dor Abdominal/etiologia , Adulto , Constrição Patológica , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/complicações , Febre/genética , Humanos , Obstrução Intestinal , Intestino Delgado , Japão , Masculino , Mutação
3.
Reumatismo ; 71(2): 85-87, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31309779

RESUMO

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.


Assuntos
Febre Familiar do Mediterrâneo/genética , Mutação , Pirina/genética , Criança , Humanos , Irã (Geográfico) , Masculino
4.
Pediatr Rheumatol Online J ; 17(1): 28, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171010

RESUMO

BACKGROUND: Relapsing periodic arthritis is a general term used for a group of diseases with recurring and periodic nature, in which the joints are intermittently involved. The aim of this study is to evaluation of the possible relationship between MEFV gene mutations in intermittent arthritis of children which has recurring and periodic nature. METHODS: In this cross-sectional study we reviewed medical records of all patients with recurrent and periodic arthritis referred to pediatric rheumatology clinic from 2003 to 2019.We excluded all patients with suspicious anamnesis and/or positive history of FMF, JIA, gout, psoriasis, IBD and SLE. The peripheral blood of these patients was screened for the 12 common pathogenic MEFV gene variants (FMF Strip Assay, Vienna lab, Vienna, Austria) according to manufacturer's instructions. RESULTS: Among 195 recorded files, 11 patients were identified with idiopathic recurrent and periodic feature. 3 patients suffering from recurrent transient synovitis hip (RSH) and 8 patients were fully compatible with the Pasero and Barbieri modified criteria of palindromic rheumatism (PR). Their mean age at diagnosis was 6.5 and 4.6 years and the average follow-up was 2.6 and 6.6 years in PR and RSH patients, respectively. The most frequently involved joints were knees and ankles in PR patients. The mean duration of attacks was 3.3 days in RSH patients and with various courses in PR. The median number of attacks was 4.75 in PR and 3 in RSH patients per year. In PR group 7 patients showed no mutations and all patients of RSH had these mutations; V726A, R761H, A744S as in heterozygote pattern. CONCLUSION: An idiopathic relapsing periodic arthritis in children with exclusively hip involvement is a MEFV gene related arthropathy; whereas with various joint attacks it could be considered as childhood PR.


Assuntos
Artrite Reumatoide/genética , Mutação/genética , Pirina/genética , Sinovite/genética , Alelos , Artrite Juvenil/genética , Criança , Pré-Escolar , Estudos Transversais , Articulação do Quadril , Humanos , Estudos Retrospectivos
5.
Clin Chim Acta ; 495: 562-569, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173732

RESUMO

BACKGROUND: Long-range PCR (LR-PCR) is used to enrich the target regions of the genome. This study aimed to establish the pipeline of targeted gene sequencing using LR-PCR and massively parallel sequencing (MPS). METHODS: The 14-kb-long MEFV gene, including the entire coding exons, was selected as a target gene and amplified using LR-PCR. The evaluated analytical factors were as follows: LR-PCR conditions, three types of post-PCR cleanup methods, and two types of MPS library preparation methods. RESULTS: With regard to LR-PCR conditions, Tks Gflex DNA polymerase at 7-min (30-s/kb) annealing/extension with 100-ng genomic DNA input had the highest yield. Regarding post-PCR purification methods, the magnetic beads-based method had high recovery and purity. In the MPS library preparation methods, the ligation-based method had a higher base coverage in the target (94.58%), uniformity of base coverage (99.95%), and target bases with no strand bias (97.40%). The exonic variants determined by Sanger sequencing were detected by both ligation- and transposon-based methods. CONCLUSIONS: Various analytical factors were evaluated, and the pipeline of targeted gene sequencing using LR-PCR and MPS was established. These data can enable the optimization of targeted gene sequencing using LR-PCR and MPS in the clinical laboratory.


Assuntos
DNA/sangue , DNA/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Diagnóstico Molecular/métodos , Pirina/genética , Sequência de Bases , Febre Familiar do Mediterrâneo/sangue , Biblioteca Gênica , Humanos , Reação em Cadeia da Polimerase em Tempo Real
6.
Immunol Med ; 42(1): 45-49, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31204589

RESUMO

A healthy 32-year-old man had a fever and elevated levels of white blood cells (WBC) and C-reactive protein (CRP). In addition, he presented with a skin rash on his forehead, around the neck, and from the anterior chest to the abdomen. His laboratory findings showed elevated levels of hepatic enzyme, CRP, and ferritin; therefore, he was suspected to have adult-onset Still's disease (AOSD) and referred to our department. We ruled out hematological malignancy and established diagnosis of AOSD according to Yamaguchi's criteria and treated with 20 mg/day prednisolone. His clinical condition did not improve, therefore, we increased the dosage of prednisolone to 40 mg/day; however, his rash gradually expanded with papules and plaques. A cervical skin biopsy revealed neutrophil dermatosis and analysis of the MEFV gene revealed a heterozygous variant in exon 2 (E148Q). We found an elevated percentage of CD86+CD14+CD16- classical monocytes in the peripheral blood using flow cytometry. We added oral potassium iodide as a treatment for neutrophil dermatosis. Despite this treatment, his eruption and fever did not subside, therefore, we changed potassium iodide to colchicine, this improved his clinical condition. This case suggests the importance of autoinflammation-related gene abnormalities and macrophage activation in the pathogenesis of neutrophil dermatosis.


Assuntos
Variação Genética , Ativação de Macrófagos , Monócitos/imunologia , Pirina/genética , Síndrome de Sweet/genética , Síndrome de Sweet/imunologia , Administração Oral , Adulto , Colchicina/administração & dosagem , Quimioterapia Combinada , Humanos , Masculino , Iodeto de Potássio/administração & dosagem , Prednisolona/administração & dosagem , Doença de Still de Início Tardio , Síndrome de Sweet/sangue , Síndrome de Sweet/tratamento farmacológico , Resultado do Tratamento
7.
Int J Immunogenet ; 46(4): 232-240, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31135083

RESUMO

Periodic fever syndromes (PFSs) are a family of clinical disorders, which are characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions. Most common types of PFSs are associated with four genes: MEFV, MVK, TNFRSF1A and NLRP3. This paper aims to add new data to the genotype-phenotype association of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. A total number of 211 patients were evaluated. Two different approaches were used for the molecular genetic evaluation of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. For the first 147 patients, Sanger sequence analysis of selected exons of MVK, TNFRSF1A and NLRP3 genes was done. For subsequent 64 patients, targeted NGS panel analysis, covering all exons of MVK, TNFRSF1A and NLRP3 genes, was used. A total number of 48 variants were detected. The "variant detection rate in index patients" was higher in the NGS group than Sanger sequencing group (19% vs. 15,1%). For the variant positive patients, a detailed genotype-phenotype table was built. In PFSs, lack of correlation exists between genotype and phenotype in the general population and even within the families. In some cases, mutations behave differently and yield unexpected phenotypes. In this study, we discussed the clinical effects of eight different variants we have detected in the MVK, TNFRSF1A and NLRP3 genes. Four of them were previously identified in patients with PFS. The remaining four were not reported in patients with PFS. Thus, we had to interpret their clinical effects by analysing their frequencies and in silico analysis predictions. We suggest that new studies are needed to evaluate the effects of these variants more clearly. To be able to demonstrate a clearer genotype-phenotype relationship, all PFS-related genes should be analysed together and the possibility of polygenic inheritance should be considered.


Assuntos
Febre Familiar do Mediterrâneo/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Éxons , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/patologia , Feminino , Febre/genética , Febre/imunologia , Febre/patologia , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Mutação , Pirina/genética
8.
Pediatr Rheumatol Online J ; 17(1): 22, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088470

RESUMO

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease in Canada and is characterized by a clinical syndrome of episodic inflammatory symptoms. Traditionally, the disease is defined by autosomal recessive inheritance of MEFV gene variants, yet FMF also not uncommonly manifests in individuals with only one identified disease-associated allele. Increasing availability and affordability of gene sequencing has led to the identification of multiple MEFV variants; however, they are often of unknown clinical significance. Variants in other genes affecting overlapping or distinct inflammatory signaling pathways - together with gene-environment interactions including epigenetic modulation - likely underlie the significant genetic and phenotypic heterogeneity seen among patients with this disease. We review recent evidence of the expanding spectrum of FMF genotype and phenotype and suggest that current drug funding schemes restricting biologic agents to patients with homozygous mutations have not kept pace with our biological understanding of the disease.


Assuntos
Febre Familiar do Mediterrâneo/genética , Terapia Biológica/métodos , Criança , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/terapia , Genótipo , Humanos , Mutação/genética , Pirina/genética , Pirina/metabolismo
9.
Intern Med ; 58(15): 2235-2240, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30996171

RESUMO

We herein report a Japanese patient with familial Mediterranean fever (FMF) who developed the clinical manifestations of mixed connective tissue disease (MCTD) and Sjögren's syndrome. The patient was a 36-year-old woman presenting with a periodic short-duration (2-3 days) fever and pleural pain. An Mediterranean fever (MEFV) gene analysis detected a complex allele mutation (P369S/R408Q) in exon 3 of the MEFV gene. Serological and clinical data showed the coexistence of MCTD and Sjögren's syndrome. Treatment with colchicine (1.0 mg/day) successfully eliminated febrile attack and pleuritis, leading to the diagnosis of FMF. Four months after the initiation of colchicine treatment, she presented with MCTD-related pulmonary artery hypertension. This is the first report of FMF coexisting with MCTD.


Assuntos
Febre Familiar do Mediterrâneo/complicações , Doença Mista do Tecido Conjuntivo/complicações , Síndrome de Sjogren/complicações , Adulto , Alelos , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Japão , Pirina/genética
10.
Rheumatol Int ; 39(6): 1099-1105, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31020337

RESUMO

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a recurrent fever syndrome for which tonsillectomy is a therapeutic option curing the disease in most patients. Recurrence after remission with tonsillectomy is extremely rare. Increasing number of reports on diverse disease manifestations in PFAPA could give us clues about the disease etiopathogenesis. We aimed to describe a patient with recurrence of PFAPA syndrome after tonsillectomy and to review the previous studies including similar cases. We report a 17-year-old boy with PFAPA syndrome who experienced remission for 3 years after tonsillectomy and was later found to harbor an MEFV mutation when the disease relapsed. He responded well to colchicine treatment at relapse. The literature review revealed 14 articles describing 24 similar PFAPA patients. The therapeutic options include single-dose corticosteroids and nonsteroidal anti-inflammatory drugs during attacks, cimetidine, and resurgery. The presented case was the only one heterozygous for an MEFV mutation and treated with colchicine at disease relapse. Albeit rare, the reoccurrence of PFAPA after tonsillectomy could occur. The presence of such patients opposes with the hypothesis that the trigger or immune dysregulation in PFAPA pathogenesis resides in tonsils.


Assuntos
Colchicina/uso terapêutico , Febre/terapia , Linfadenopatia/terapia , Faringite/terapia , Estomatite Aftosa/terapia , Tonsilectomia , Moduladores de Tubulina/uso terapêutico , Adolescente , Febre/complicações , Heterozigoto , Humanos , Linfadenopatia/complicações , Masculino , Pescoço , Faringite/complicações , Pirina/genética , Recidiva , Estomatite Aftosa/complicações , Síndrome
12.
PLoS Genet ; 15(4): e1008038, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946743

RESUMO

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Espondilite Anquilosante/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Febre Familiar do Mediterrâneo/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Humanos , Interleucina-1beta/sangue , Interleucina-23/sangue , Irã (Geográfico) , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , Turquia
13.
Turk J Med Sci ; 49(2): 472-477, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30887796

RESUMO

Background/aim: The distribution of Mediterranean fever (MEFV) gene mutations in Turkish familial Mediterranean fever (FMF) patients varies according to geographic area of Turkey. There is a need for highly representative data for Turkish FMF patients. The aim of our study was to investigate the distribution of the common MEFV mutations in Turkish FMF patients in a nationwide, multicenter study. Materials and methods: Data of the 2246 FMF patients, from 15 adult rheumatology clinics located in different parts of the country, were evaluated retrospectively. The following mutations have been tested in all patients: M694V, M680I, M694I, V726A, and E148Q. Results: There were 1719 FMF patients with available genetic testing. According to the genotyping, homozygous M694V, present in 413 patients (24%), was the most common mutation . One hundred and fifty-four (9%) of patients had no detectable mutations. Allele frequencies of common mutations were: M694V (n = 1529, 44.5%), M680I (n = 423, 12.3%), V726A (n = 315, 9.2%), E148Q (n = 214, 1%), and M694I (n = 12, <1%). Conclusion: In this large-scale multicenter study, we provided information about the frequencies of common MEFV gene mutations obtained from adult Turkish FMF patients. Nearly half of the patients were carrying at least one M694V mutations in their alleles.


Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Genética Populacional , Mutação/genética , Pirina/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Testes Genéticos , Genética Populacional/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Estudos Retrospectivos , Turquia/epidemiologia , Adulto Jovem
14.
Clin Rheumatol ; 38(7): 1947-1952, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30826945

RESUMO

OBJECTIVE: To explore the frequency of MEFV gene mutations in children with Henoch-Schönlein purpura who had no prior familial Mediterranean fever diagnosis and to evaluate the association of MEFV mutations with the clinical and laboratory features of Henoch-Schönlein purpura. METHODS: Data of 1120 patients diagnosed with Henoch-Schönlein purpura were reviewed retrospectively. The spectrum and degree of organ involvement and acute phase reactant levels were documented for each patient. Blood for MEFV gene mutation analysis was obtained either at the time of the Henoch-Schönlein purpura diagnosis or during follow-up visits. Pathological specimens of patients who underwent biopsy (renal/skin) were evaluated with special consideration for immunofluorescent examinations. RESULTS: Two hundred and thirty-eight (21.3%) patients were found to have one of the MEFV mutations in which exon 10 mutations were the most common (16.7%). Abdominal pain, joint involvement, scrotal involvement, and relapse were more frequent, and acute-phase reactant levels were significantly high in patients with MEFV mutations. More severe characteristics were observed in the presence of homozygous exon 10 mutations. There was no significant association between exon 2 variants and clinical course of Henoch-Schönlein purpura. Patients carrying MEFV mutations did not have significantly higher levels of IgA deposits in the biopsy materials. CONCLUSION: Henoch-Schönlein purpura in patients with homozygous exon 10 MEFV mutations seems to be more severe than that in patients carrying other mutations. In patients with exon 10 MEFV mutations, Henoch-Schönlein purpura might be considered as an associated presentation of familial Mediterranean fever rather than a separate clinical entity. Key points • p.M694V mutation is more common in Henoch-Schönlein purpura than in the general population. • p.E148Q variants have no impact on clinical symptoms and laboratory findings in Henoch-Schönlein purpura patients. • The majority of Henoch-Schönlein purpura patients with familial Mediterranean fever have no IgA deposits. • Henoch-Schönlein purpura in familial Mediterranean fever patients may be considered as an integral clinical feature of familial Mediterranean fever.


Assuntos
Mutação , Púrpura de Schoenlein-Henoch/genética , Púrpura de Schoenlein-Henoch/patologia , Pirina/genética , Adolescente , Proteína C-Reativa/análise , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/genética , Feminino , Homozigoto , Humanos , Masculino , Estudos Retrospectivos
15.
Rheumatol Int ; 39(5): 911-919, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30783801

RESUMO

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.


Assuntos
Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/genética , Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleosídeos/genética , Osteomielite/diagnóstico , Osteomielite/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pirina/genética , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adulto Jovem
16.
J Clin Lab Anal ; 33(4): e22852, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30714637

RESUMO

BACKGROUND: Familial Mediterranean fever (FMF) is the most common hereditary monogenic autoinflammatory disease caused by mutations in the MEFV gene. It is controversial whether E148Q alteration is an insignificant variant or a disease-causing mutation. The aim of this study was to evaluate the clinical features and disease severity of FMF patients carrying E148Q mutation. METHODS: Files of FMF patients were retrospectively evaluated. Patients with at least one E148Q mutation were included to the study. The clinical characteristics and disease severity of the patients who were carrying only E148Q mutation were compared with the patients who were compound heterozygous for E148Q and homozygous for M694V mutation. RESULTS: The study group comprised 33 patients who were homozygous or heterozygous for E148Q; 34 with compound heterozygous E148Q mutations and 86 patients who had homozygous M694V mutation. Patients who had only E148Q mutation were found to have the oldest mean age of disease onset and lowest mean disease severity score. Attack frequency and colchicine doses were lower in patients with only E148Q mutation as compared with the other two groups. The frequency of clinical findings such as fever, abdominal pain, arthralgia, and arthritis among the three groups was similar. CONCLUSION: Familial Mediterranean fever patients with only E148Q mutation are presenting with late-onset and milder disease course despite having similar clinical findings as compared with patients who had other mutations. Finally, we imply that E148Q is a mutation and colchicine treatment should be given.


Assuntos
Febre Familiar do Mediterrâneo/etiologia , Mutação , Pirina/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Colchicina/uso terapêutico , Éxons , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
17.
Presse Med ; 48(1 Pt 2): e61-e76, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30686512

RESUMO

Familial Mediterranean Fever (FMF) is the oldest and the most frequent of all described hereditary periodic fever syndromes. The populations originating from Mediterranean basin carry the highest risk for FMF however it is being increasingly recognized in many parts of the world. It is an autoinflammatory disease with an autosomal recessive transmission. In the majority of the patients it is related with mutations in the MEFV gene that encodes a protein named pyrin. This protein has been shown to act as a regulator of inflammation mediated by IL-1ß, which plays a major role in the pathogenesis of FMF. Approximately one-third of the patients have either a single or no mutation which raise questions about its mode of inheritance. FMF is a clinical diagnosis and characterized by self-limited bouts of fever and serositis. The main long-term complication of the disease is AA amyloidosis. The mainstay of treatment is life-long colchicine given daily to prevent the recurrence of febrile attacks and the development of amyloidosis. Patients with insufficient response to colchicine may be treated with anti IL-1 agents.


Assuntos
Febre Familiar do Mediterrâneo , Idade de Início , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Feminino , Estudos de Associação Genética , Humanos , Imunidade Inata , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Masculino , Gravidez , Complicações na Gravidez/genética , Pirina/deficiência , Pirina/genética , Pirina/fisiologia
18.
Intern Med ; 58(7): 1017-1022, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568124

RESUMO

We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis. Because her mother also had cold-induced urticaria and her skin lesions histologically showed neutrophilic dermatitis, we suspected that she had familial cold autoinflammatory syndrome, a subtype of cryopyrin-associated periodic syndromes. Sequencing of the NLRP3 and MEFV genes revealed that she carried both the p.A439V missense mutation and p.E148Q homozygous mutation, which is commonly detected in familial Mediterranean fever patients. The administration of colchicine reduced the frequency and severity of her skin rash and leg edema.


Assuntos
Síndromes Periódicas Associadas à Criopirina/diagnóstico , DNA/genética , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pirina/genética , Idoso , Biópsia , Síndromes Periódicas Associadas à Criopirina/genética , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/genética , Feminino , Homozigoto , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirina/metabolismo , Doenças Raras
19.
J Clin Rheumatol ; 25(2): 69-73, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29596210

RESUMO

BACKGROUND/OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent, self-limited attacks of fever with serositis. Various diseases were reported to be associated with FMF. The aim of this study was to investigate the frequency and characteristics of sacroiliitis in children with FMF. METHODS: Files of FMF patients who had been seen in 2 reference hospitals in Ankara were retrospectively evaluated. Patients with FMF and concomitant sacroiliitis were included to the study. All patients had magnetic resonance imaging evidence of sacroiliitis. RESULTS: Among 650 FMF patients, 17 (11 females, 6 males; mean age, 13.32 ± 4.24 years) (2.6%) of them were found to have sacroiliitis. Familial Mediterranean fever diagnosis was done prior to sacroiliitis diagnosis in 11 patients (65%) and concurrently or afterward in 6 patients (35%). Ten patients had isolated sacroiliitis, and 7 had associated diseases (5 enthesitis-related arthritis, 1 psoriatic arthritis, and 1 ulcerative colitis). Arthritis (59%), arthralgia (77%), leg pain (71%), heel pain (41%), and enthesitis (29%) were common complaints. Sacroiliac tenderness was detected in 77%, and M694V mutation in almost 90% of the patients. All patients received colchicine therapy. Additionally, 14 of them were treated with nonsteroidal anti-inflammatory drugs, 10 were on sulfasalazine treatment, and 7 of them were on biological agents. CONCLUSIONS: Sacroiliitis can be seen in patients with FMF during childhood, and M694V mutation seems to be a susceptibility factor for its development. Inflammatory low-back pain and leg and heel pain could suggest sacroiliitis.


Assuntos
Febre Familiar do Mediterrâneo/complicações , Sacroileíte/epidemiologia , Adolescente , Criança , Febre Familiar do Mediterrâneo/diagnóstico por imagem , Febre Familiar do Mediterrâneo/genética , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Pirina/genética , Estudos Retrospectivos , Sacroileíte/diagnóstico , Sacroileíte/genética , Turquia , Adulto Jovem
20.
Postgrad Med ; 131(1): 68-72, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30513227

RESUMO

OBJECTIVES: Henoch-Schönlein purpura (HSP) is characterized by non-thrombocytopenic palpable purpura, abdominal pain, and arthralgia/arthritis. We aimed to describe the clinical presentations of children with HSP in a single center and compare the prevalence of each manifestations between patients with MEFV variants, particularly in exon 10 and those without. METHODS: This cohort retrospectively included 144 HSP (59 females, 85 males) patients without Familial Mediterranean Fever (FMF) symptoms and followed for at least 6 months. We utilized the MEFV gene sequencing by using next-generation sequencing platform (MiSeq System, Illumina). RESULTS: At least one MEFV variant was detected in 73 (50.7%) of 144 HSP patients and 5 (3.5%) patients were homozygote for M694V mutation. Although severe gastrointestinal involvement and nephritis rates were similar, we found that serum IgA, leukocyte, and platelet count at diagnosis were higher and hemoglobin was lower in HSP patients with MEFV gene variants in exon 10 than those without. Additionally, HSP patients with MEFV variants in exon 10 more often present with abdominal pain and intussusception. CONCLUSION: MEFV variants in exon 10 may affect clinical presentation of HSP in populations where FMF is common. While HSP may be an initial symptom of FMF, we speculate that physicians should be aware of FMF possibility in children with intussusception and lower hemoglobin, higher serum IgA, leukocyte, and platelet count.


Assuntos
Púrpura de Schoenlein-Henoch/genética , Pirina/genética , Adolescente , Criança , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Prevalência , Púrpura de Schoenlein-Henoch/diagnóstico , Estudos Retrospectivos
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