RESUMEN
A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (MEFV) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in MEFV as shown by genetic testing performed between 2001 and 2017. We introduced the term 'origin score' to capture the dose and different combinations of the grandparents' origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common MEFV variant types and a geographical region. A strong geographic association could arise from positive selection of a specific MEFV variant conferring resistance to endemic infectious agents.
Asunto(s)
Fiebre Mediterránea Familiar , Fiebre Mediterránea Familiar/complicaciones , Fiebre Mediterránea Familiar/genética , Humanos , Israel , Judíos , Aprendizaje Automático , Mutación , Pirina/genéticaRESUMEN
OBJECTIVES: FMF results from mutations in the Mediterranean fever (MEFV) gene. The p. E148Q protein alternation is one of the most frequent in the MEFV gene, yet the exact E148Q genotype-phenotype correlation remains unclear. The aim of this study was to examine clinical significance of heterozygous E148Q variant in a paediatric FMF cohort. METHODS: We compared the clinical manifestations and disease severity score of four genetic subgroups: (group 1) patients harbouring a single heterozygous p. E148Q variant (n = 6); (group 2) patients harbouring a single p. M694V heterozygous variant (n = 88); (group 3) patients harbouring compound heterozygous p. M694V and p. E148Q variants (n = 36); and (group 4) homozygotes for p. M694V variant (n = 160). RESULTS: Of 646 FMF children from our centre, only 1% (six patients) of our genetically characterized FMF cohort had a single E148Q variant, most presenting with recurrent fevers and abdominal pain. None of the participants was found to harbour homozygous E148Q. Overall, M694V/E148Q compound heterozygosity did not exhibit a more severe phenotype compared with patients with a single M694V variant. The former group were less likely to have abdominal pain and exertional leg pain (P < 0.004 and P < 0.001, respectively) and more likely to have chest pain (P < 0.01). Both subgroups showed milder clinical phenotype compared with patients with M694V homozygosity. CONCLUSION: Our findings demonstrate that a single heterozygous E148Q variant is unlikely to cause FMF in children and that E148Q/M694V is clinically indistinguishable from a single M694V variant. Thus, E148Q heterozygosity does not result in clinically meaningful phenotype in children.
Asunto(s)
Fiebre Mediterránea Familiar/genética , Pirina/genética , Sustitución de Aminoácidos , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Masculino , Estudios RetrospectivosRESUMEN
The penetrance of the p.[Met694Val];[Met694Val] genotype of pyrin in adult familial Mediterranean fever (FMF) patients is close to 100%. Disease penetrance of the p.[Met694Val];[Glu148Gln] genotype (M694V/E148Q), and the heterozygous p.[Met694Val];[=] genotype is unknown. A difference in the penetrance of the latter two may indicate functionality for the p.Glu148Gln variant. We performed a penetrance estimation study using controls and patients of North African Jewish (NAJ) decent. FMF in this population is highly prevalent and mutation frequencies are well known. The ratio between the calculated frequencies of the three genotypes obtained from the control cohort and the actual frequency obtained from the patient cohort were used to determine the penetrance of p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=]. We found a penetrance of 0.135 and 0.008 for p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=], respectively. Thus, the penetrance of p.[Met694Val];[Glu148Gln] is more than 17 times higher than p.[Met694Val];[=], indicating an active role for p.Glu148Gln when combined with p.Met694Val.
Asunto(s)
Fiebre Mediterránea Familiar/genética , Penetrancia , Pirina/genética , África del Norte , Estudios de Cohortes , Genotipo , Heterocigoto , Humanos , Judíos/genéticaRESUMEN
BACKGROUND: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. METHODS: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. RESULTS: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. CONCLUSIONS: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
Asunto(s)
Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Desaminasa/genética , Proteínas del Citoesqueleto/genética , Pruebas Genéticas , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Proteína Adaptadora de Señalización NOD2/genética , Guías de Práctica Clínica como Asunto , Diagnóstico Prenatal , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genéticaRESUMEN
INTRODUCTION: In this case report we discuss a patient who suffers from recurrent bouts of fever and as part of the clinical workup for autoinflammatory diseases was genetically tested for mutations in 26 genes related to autoinflammatory disease with a next generation sequencing test. We discuss the benefits and pitfalls of using this test.
Asunto(s)
Fiebre de Origen Desconocido , Enfermedades Autoinflamatorias Hereditarias , Humanos , Hipertermia Inducida , MutaciónRESUMEN
Monogenic autoinflammatory disorders (AIDs) are rare diseases caused by variants in genes regulating the innate immune system. The identification of the first four genes responsible for the prototype group of hereditary recurrent fevers prompted the development of genetic diagnosis, followed by external quality assessment and guidelines for the interpretation of sequence variants in these diseases. Recent changes in the diagnosis of genetic diseases, namely the implementation of next-generation sequencing (NGS), lead to discovery of the new genes associated with at least 40 novel AIDs, which revolutionized patient care and prognosis. However, these rapid advances resulted in nonstandardized molecular strategies that can influence genetic diagnosis and reporting of results. In order to assess factors, which may have an impact on performance and quality of results in the NGS era, we carried out an online survey among member laboratories of the European Molecular Genetics Quality Network, which highlighted different strategies being used and identified pitfalls that deserve discussion and improvement.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Pautas de la Práctica en Medicina , Europa (Continente) , Estudios de Asociación Genética/métodos , Pruebas Genéticas/métodos , Humanos , Vigilancia en Salud Pública , Encuestas y CuestionariosRESUMEN
BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Asunto(s)
Predisposición Genética a la Enfermedad/epidemiología , Enfermedades Autoinflamatorias Hereditarias/clasificación , Enfermedades Autoinflamatorias Hereditarias/genética , Deficiencia de Mevalonato Quinasa/clasificación , Sistema de Registros , Consenso , Estudios Transversales , Europa (Continente) , Fiebre Mediterránea Familiar/clasificación , Fiebre Mediterránea Familiar/epidemiología , Fiebre Mediterránea Familiar/genética , Femenino , Enfermedades Autoinflamatorias Hereditarias/epidemiología , Humanos , Masculino , Deficiencia de Mevalonato Quinasa/diagnóstico , Deficiencia de Mevalonato Quinasa/epidemiología , Deficiencia de Mevalonato Quinasa/genética , Prevalencia , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing. OBJECTIVES: This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes: MEFV, TNFRSF1A, NLRP3 and MVK. METHODS: We configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds. RESULTS: Consensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFV gene. CONCLUSION: Applying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http://github.com/molgenis/molgenis; the specific HRF configuration is available at http://molgenis.org/said/. The HRF pathogenicity classifications will be published on the INFEVERS database at https://fmf.igh.cnrs.fr/ISSAID/infevers/.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Flujo de Trabajo , Alelos , Biología Computacional/métodos , Consenso , Bases de Datos Genéticas , Manejo de la Enfermedad , Estudios de Asociación Genética/métodos , Pruebas Genéticas , Humanos , Fenotipo , Guías de Práctica Clínica como Asunto , Navegador WebRESUMEN
OBJECTIVE: Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested as recurrent serosal inflammation. An association between FMF and malignancy has not been evaluated. The aim of this study was to estimate cancer risk in a large cohort of FMF patients from a single institution. METHODS: The study cohort consisted of 8,534 FMF patients registered at the National FMF Center in Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and then stratified by age and sex. Standardized incidence ratios (SIRs) for cancers were calculated. RESULTS: Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970-2011. The overall cancer risk among patients with FMF was significantly lower than was expected in specific sex and ethnic groups of the Israeli population: for males of Jewish ethnicity, SIR 0.66 (95% confidence interval [95% CI] 0.55-0.77), P < 0.001; for females of Jewish ethnicity, SIR 0.75 (95% CI 0.64-0.86), P < 0.001; and for males of Arab ethnicity, SIR 0.34 (95% CI 0.07-0.99), P = 0.024. CONCLUSION: FMF patients have a significantly lower incidence of cancer than the general population of Israel. This pattern was demonstrated in 2 ethnic populations: Jewish and Arab. We speculate that the lower cancer incidence could be attributed to a direct physiologic effect of FMF or to its treatment.
Asunto(s)
Fiebre Mediterránea Familiar/complicaciones , Neoplasias/epidemiología , Adulto , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Israel/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Sistema de Registros , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVES: Cryopyrin associated periodic syndromes (CAPS) comprise a spectrum of autoinflammatory disorders of varying severity caused by mutations in the NLRP3 gene. The NLRP3-Q703K allele has been reported both as a functional polymorphism and as a low penetrance mutation. METHODS: To describe the clinical phenotype of subjects with the Q703K allele and to report the frequency of this allele among patients with autoinflammatory symptoms and healthy controls. To this end, a cohort of 10 ethnically-matched controls per each Q703K-carrying patient, was composed. RESULTS: Ninety patients suspected of harboring a systemic autoinflammatory disease (SAID), exclusive of FMF, were referred to our center for genotyping between 2012 and 2015. Fourteen of them (15.5%) were found to carry the Q703K allele, compared to 22 of 130 (16.9%) healthy, ethnically matched controls. CONCLUSIONS: The similar carrier rate of the NLRP3-Q703K allele among patients with manifestations of a SAID and an ethnically matched control group suggest that this variant, does not determine the clinical phenotype. This reiterates the importance of testing a control group to avoid erroneously attributing a causative role to a gene polymorphism.
Asunto(s)
Síndromes Periódicos Asociados a Criopirina/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Polimorfismo Genético , Estudios de Casos y Controles , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/etnología , Síndromes Periódicos Asociados a Criopirina/inmunología , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Israel/epidemiología , Epidemiología Molecular , Fenotipo , Factores de RiesgoRESUMEN
BACKGROUND: Postpericardiotomy syndrome (PPS) is characterized by pleuro-pericardial inflammation, which occurs in patients undergoing surgical procedures involving the pleura, pericardium, or both. The syndrome is considered to be immune mediated. However, its pathogenesis is not fully understood. It has previously been demonstrated that the Mediterranean Fever (MEFV) gene, which is associated with familial Mediterranean fever (FMF), has a role in the activation and expression of several inflammatory diseases. OBJECTIVES: To investigate whether carriage of the MEFV mutation may precipitate PPS or affect its phenotype. METHODS: The study population included 45 patients who underwent cardiac surgery and developed PPS. The control group was comprised of 41 patients who did not develop PPS. Clinical and demographic data was collected. The severity of PPS was evaluated. Genetic analysis to determine the carriage of one the three most common MEFV gene mutations (M694V, V726A, E148Q) was performed. The carriage rate of MEFV mutations in patients with and without PPS was compared. Association between MEFV mutation carriage and severity of PPS was evaluated. RESULTS: The rate of mutation carriage in the MEFV gene was similar in patients with and without PPS (15.6% in the study groups vs. 29.3% in the control group, P = 0.1937). The rate of mutation carriage in the MEFV gene was significantly lower among patients with severe PPS as compared to patients with mild-moderate PPS (4.8% vs. 25%, P < 0.05). CONCLUSIONS: Carriage of mutations in the MEFV gene is not associated with development of PPS; however, it may affect PPS severity.
Asunto(s)
Mutación , Síndrome Pospericardiotomía/genética , Pirina/genética , Estudios de Casos y Controles , Proteínas del Citoesqueleto , Fiebre Mediterránea Familiar/genética , Humanos , Síndrome Pospericardiotomía/etiologíaRESUMEN
There is a growing body of literature documenting dreams, visions, and other trans-personal communications that occur as part of the dying process, often called end-of-life dreams and visions (ELDVs) or deathbed communications (DBCs). This paper describes a unique case involving distressing visions at the end of life, provides a review of existing literature around ELDVs, and will provide a framework within which to approach the patient experiencing distressing ELDVs.
Asunto(s)
Sueños/psicología , Ilusiones/psicología , Cuidado Terminal/psicología , Enfermo Terminal/psicología , Anciano , Resultado Fatal , Humanos , Neoplasias Pulmonares/psicología , MasculinoRESUMEN
BACKGROUND: A study was designed to identify the source of fever in a patient with post-polycythemia myelofibrosis, associated with clonal Janus Kinase 2 (JAK2) mutation involving duplication of exon 12. The patient presented with 1-2 day long self-limited periodic episodes of high fever that became more frequent as the hematologic disease progressed. METHODS: After ruling out other causes for recurrent fever, analysis of the pyrin encoding Mediterranean fever gene (MEFV) was carried out by Sanger sequencing in peripheral blood DNA samples obtained 4 years apart, in buccal cells, laser dissected kidney tubular cells, and FACS-sorted CD3-positive or depleted mononucleated blood cells. Hematopoeitc cells results were validated by targeted deep sequencing. A Sanger sequence based screen for pathogenic variants of the autoinflammatory genes NLRP3, TNFRSF1A and MVK was also performed. RESULTS: A rare, c.1955G>A, p.Arg652His MEFV gene variant was identified at negligible levels in an early peripheral blood DNA sample, but affected 46 % of the MEFV alleles and was restricted to JAK2-positive, polymorphonuclear and CD3-depleted mononunuclear DNA samples obtained 4 years later, when the patient experienced fever bouts. The patient was also heterozygous for the germ line, non-pathogenic NLRP3 gene variant, p.Q705K. Upon the administration of colchicine, the gold standard treatment for familial Mediterranean fever (FMF), the fever attacks subsided. CONCLUSIONS: This is the first report of non-transmitted, acquired FMF, associated with a JAK2 driven clonal expansion of a somatic MEFV exon 10 mutation. The non-pathogenic germ line NLRP3 p.Q705K mutation possibly played a modifier role on the disease phenotype.
Asunto(s)
Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/genética , Janus Quinasa 2/genética , Mutación , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Biopsia , Células Clonales , Colchicina/uso terapéutico , Exones/genética , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Femenino , Supresores de la Gota/uso terapéutico , Humanos , Persona de Mediana Edad , Policitemia Vera/diagnóstico , Policitemia Vera/tratamiento farmacológico , Polimorfismo de Longitud del Fragmento de Restricción , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , PirinaRESUMEN
OBJECTIVE: Reactive (AA) amyloidosis may complicate familial Mediterranean fever (FMF), the prototype of autoinflammatory diseases. Thus, proteinuria in FMF is commonly viewed as resulting from amyloidosis, and kidney biopsy is deemed superfluous. However, nephropathy other than amyloidosis has been described in FMF, but its rate and distinctive characteristics are unknown. Our aim was to determine the rate and underlying pathology of FMF-related nonamyloidotic proteinuria and compare its clinical course, demographic, and genetic features to those of FMF-amyloid nephropathy. METHODS: This study is a retrospective analysis of data from patients with FMF undergoing kidney biopsy for proteinuria above 0.5 g/24 h, over 10 years (2001-2011). Clinical, laboratory, genetic, and pathology data were abstracted from patient files. Biopsies were viewed by an experienced pathologist, as necessary. RESULTS: Of the 25 patients referred for kidney biopsy, only 15 (60%) were diagnosed with amyloid kidney disease (AKD), and 10 were diagnosed with another nephropathy. The AKD and nonamyloid kidney disease (NAKD) groups were comparable on most variables, but showed distinct characteristics with regard to the degree of proteinuria (6.45 ± 4.3 g vs 2.14 ± 1.6 g, p = 0.006), rate of severe FMF (14 vs 5 patients, p = 0.022), and rate of development of end stage renal disease (73.3% vs 20%, p = 0.015), respectively. CONCLUSION: NAKD is common in FMF and, compared to amyloidosis, it is featured with milder course and better prognosis. Contrary to common practice, it is highly recommended to obtain a kidney biopsy from patients with FMF and proteinuria more than 0.5 g/24 h.
Asunto(s)
Lesión Renal Aguda/etiología , Amiloidosis/etiología , Fiebre Mediterránea Familiar/complicaciones , Proteinuria/etiología , Lesión Renal Aguda/patología , Adulto , Amiloidosis/patología , Biopsia , Fiebre Mediterránea Familiar/patología , Femenino , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Proteinuria/patología , Sistema de Registros/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
The high carriage rate of MEFV mutations in at risk populations suggests that they confer a selective advantage, possibly by way of protection from infections. Here, we sought to assess whether this putative protection contributes to longevity, by studying MEFV mutation status in nonagenarians and the association of mutation carriage with life-threatening conditions. DNA samples and a medical history questionnaire were obtained from 200 nonagenarians (>90 years of age), who received medical treatment at a large tertiary hospital in Israel. The prevalence of MEFV mutations in the study group was compared to the known prevalence, by ethnic group, in the Israeli population. The presence of associated diseases in mutation carriers versus noncarriers was compared. The majority of study subjects were females (67.5 %) of Ashkenazi origin (78%). A fifth carried an MEFV mutation, most commonly E148Q (73% of total mutations), followed by V726A (5%). Only the frequency of E148Q in Ashkenazi subjects was found to be higher than expected in the general Ashkenazi population (19.8 vs. 2.6%, p < 0.0001). Cardiac arrhythmias and hypothyroidism were more common in mutation carriers, while no difference was noted, between carriers and noncarriers, in the rates of ischemic heart disease, diabetes, stroke and a wide range of other serious conditions. Our findings suggest that E148Q carriage contributes to longevity in the Ashkenazi population, perhaps by enhancing resistance to infections.
Asunto(s)
Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/genética , Anciano de 80 o más Años , Arritmias Cardíacas/genética , Análisis Mutacional de ADN , Fiebre Mediterránea Familiar/epidemiología , Femenino , Humanos , Hipotiroidismo/genética , Israel , Judíos/genética , Longevidad/genética , Masculino , Mutación , Prevalencia , PirinaRESUMEN
OBJECTIVE: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders, associated with genes (MEFV and NOD2/CARD15, respectively) encoding for regulatory proteins, important in innate immunity, apoptosis, cytokine processing, and inflammation. Although mutations in the MEFV gene were shown to modify Crohn's disease, the role of NOD2/CARD15 gene mutations in the FMF disease phenotype was never studied before. PATIENTS AND METHODS: The cohort consisted of 103 consecutive children with FMF, followed in a single referral center. NOD2/CARD15 genotypes were analyzed in all patients and 299 ethnically matched unaffected controls. Demographic data, clinical characteristics, and disease course of FMF patients with and without NOD2/CARD15 mutation were compared. RESULTS: A single NOD2/CARD15 mutation was detected in 10 (9.7%) FMF patients and 26 (8.7%) controls. No homozygous or compound heterozygous subjects were discovered in the 2 groups. FMF patients carrying a NOD2/CARD15 mutation had a higher rate of erysipelas-like erythema and acute scrotum attacks, a trend for a higher rate of colchicine resistance and a more severe disease as compared with patients without mutations. CONCLUSIONS: NOD2/CARD15 mutations are not associated with an increased susceptibility to develop FMF. Nevertheless, the presence of these mutations in FMF patients appears to be associated with a trend to a more severe disease.
Asunto(s)
Fiebre Mediterránea Familiar/genética , Predisposición Genética a la Enfermedad , Mutación , Proteína Adaptadora de Señalización NOD2/genética , Enfermedad Aguda , Preescolar , Estudios de Cohortes , Colchicina/uso terapéutico , Resistencia a Medicamentos , Eritema/etiología , Eritema/patología , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Femenino , Humanos , Masculino , Pronóstico , Escroto/patología , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic syndrome (TRAPS) mutation in patients with familial Mediterranean fever (FMF) and to study the role of this mutation in FMF. METHODS: Ninety-two FMF patients and 250 controls were genotyped for the R92Q mutation. The frequency of R92Q was assessed among 5 groups of FMF patients. RESULTS: R92Q was found in 6% of the controls, with an especially high carrier rate among Moroccan Jews (8%). R92Q was found in 3 (3.2%) of the 92 FMF patients, 1 homozygous for the MEFV M694V mutation and 2 heterozygous for M694V. All 3 patients showed partial response to colchicine. R92Q was not found in patients unresponsive to colchicine, nor was it found in patients with amyloidosis or in patients with FMF-like disease without MEFV mutations. CONCLUSION: The frequency of the R92Q mutation in FMF patients is comparable with that of controls. Despite the fact that TRAPS and FMF share common biochemical pathways, we found no evidence for an interaction between these two genes.
Asunto(s)
Fiebre Mediterránea Familiar/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Adolescente , Adulto , Estudios de Casos y Controles , Fiebre Mediterránea Familiar/clasificación , Fiebre Mediterránea Familiar/etnología , Femenino , Humanos , Masculino , Mutación , Valores de ReferenciaRESUMEN
OBJECTIVE: To characterize the clinical and genetic features of familial Mediterranean fever (FMF). STUDY DESIGN: Clinical presentation and MEditerranean FeVer mutation type of all patients with FMF, who first manifested the disease at < or =2 years of age were analyzed and compared with patients who first presented with FMF between 2 and 16 years. RESULTS: Of 814 patients with FMF, in 254 patients (31.2%) the first FMF attack was at < or =2 years of age, with a mean age at onset of 1.1 +/- 0.8 years. They were compared with 242 patients who presented with their first manifestation of FMF at 2 to 16 years. The clinical manifestations of FMF were comparable in the 2 patient groups, but the delay of diagnosis was longer in patients with early presentation (3.2 +/- 3.2 years vs.1.9 +/- 2.7 years in the group with onset at 2-16 years, P < .001). A subgroup of patients (60/254), who were diagnosed at < or =2 years had the highest rate of attacks of fever alone as their sole manifestation (40.0% vs 8.4%, P < .05), and less peritonitis (45% vs 86.1%, P < .05) and pleuritis (3.4% vs 32.9%, P < .05). Most of these patients were homozygous for the M694V mutation and were of North African (Sephardic Jewish) extraction. CONCLUSION: In early life, FMF often begins with an atypical presentation, characterized by attacks of fever alone, and its diagnosis and initiation of treatment is therefore significantly delayed.
Asunto(s)
Fiebre Mediterránea Familiar/diagnóstico , Adolescente , Edad de Inicio , Niño , Preescolar , Proteínas del Citoesqueleto/genética , Análisis Mutacional de ADN , Fiebre Mediterránea Familiar/epidemiología , Fiebre Mediterránea Familiar/genética , Femenino , Humanos , Lactante , Masculino , Mutación , Fenotipo , PirinaRESUMEN
OBJECTIVE: Familial Mediterranean fever (FMF) is an inherited disease characterized by attacks of febrile polyserositis. In children, attacks of fever alone, or with headache and malaise, may precede other forms of attacks. Our objective was clinical and genetic characterization of FMF and its development in pediatric patients who first presented with attacks of fever alone. METHODS: Clinical characterization and MEFV genotype of all FMF patients < 16 years of age at disease onset and first presenting with attacks of fever alone were analyzed and compared for age, sex, and disease duration with matched FMF patients presenting with serositis at the onset of the disease. RESULTS: There were 814 patients with FMF in our registry. Fifty patients formed the study group and 234 patients the control group. In the study group, the first (febrile) attacks appeared at a younger age than in the control group (1.7 +/- 1.6 yrs vs 5.0 +/- 4.1 yrs, respectively; p < 0.0001), diagnosis was made earlier (4.2 +/- 2.7 yrs vs 6.7 +/- 4.1 yrs; p < 0.0001), despite a trend for a longer delay in diagnosis. In the study group, attacks were shorter (1.6 +/- 0.8 days vs 2.1 +/- 1.0 days; p = 0.023) and homozygosity to the M694V mutation was more prevalent (46% vs 31%; p = 0.03). Attack rate, colchicine dose, and the MEFV mutation carrier rates were comparable between the groups. In 40/50 (80%) of the patients with fever alone, serositis had developed over a course of 2.9 +/- 2.2 years after disease onset. CONCLUSION: FMF in young children may begin with attacks of fever alone, but it progresses to typical FMF disease over the next 2.9 +/- 2.2 years. Our study demonstrates that clinical heterogeneity at presentation is more likely to indicate a feature of a disease in development, rather than to mark distinct phenotypes of FMF.