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2.
Proc Natl Acad Sci U S A ; 116(39): 19736-19742, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31501327

RESUMO

Meristems are highly regulated structures ultimately responsible for the formation of branches, lateral organs, and stems, and thus directly affect plant architecture and crop yield. In meristems, genetic networks, hormones, and signaling molecules are tightly integrated to establish robust systems that can adapt growth to continuous inputs from the environment. Here we characterized needle1 (ndl1), a temperature-sensitive maize mutant that displays severe reproductive defects and strong genetic interactions with known mutants affected in the regulation of the plant hormone auxin. NDL1 encodes a mitochondria-localized ATP-dependent metalloprotease belonging to the FILAMENTATION TEMPERATURE-SENSITIVE H (FTSH) family. Together with the hyperaccumulation of reactive oxygen species (ROS), ndl1 inflorescences show up-regulation of a plethora of stress-response genes. We provide evidence that these conditions alter endogenous auxin levels and disrupt primordia initiation in meristems. These findings connect meristem redox status and auxin in the control of maize growth.

3.
Ann Rheum Dis ; 78(8): 1025-1032, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31018962

RESUMO

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.

4.
J Rheumatol ; 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385706

RESUMO

OBJECTIVE: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF. METHODS: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1. RESULTS: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF. CONCLUSION: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

5.
Pediatr Rheumatol Online J ; 16(1): 27, 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29669569

RESUMO

BACKGROUND: Diagnosis of Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is currently based on a set of criteria proposed in 1999 modified from Marshall's criteria. Nevertheless no validated evidence based set of classification criteria for PFAPA has been established so far. The aim of this study was to identify candidate classification criteria PFAPA syndrome using international consensus formation through a Delphi questionnaire survey. METHODS: A first open-ended questionnaire was sent to adult and pediatric clinicians/researchers, asking to identify the variables thought most likely to be helpful and relevant for the diagnosis of PFAPA. In a second survey, respondents were asked to select, from the list of variables coming from the first survey, the 10 features that they felt were most important, and to rank them in descending order from most important to least important. RESULTS: The response rate to the first and second Delphi was respectively 109/124 (88%) and 141/162 (87%). The number of participants that completed the first and second Delphi was 69/124 (56%) and 110/162 (68%). From the first Delphi we obtained a list of 92 variables, of which 62 were selected in the second Delphi. Variables reaching the top five position of the rank were regular periodicity, aphthous stomatitis, response to corticosteroids, cervical adenitis, and well-being between flares. CONCLUSION: Our process led to identification of features that were felt to be the most important as candidate classification criteria for PFAPA by a large sample of international rheumatologists. The performance of these items will be tested further in the next phase of the study, through analysis of real patient data.


Assuntos
Febre/diagnóstico , Linfadenite/diagnóstico , Faringite/diagnóstico , Estomatite Aftosa/diagnóstico , Criança , Pré-Escolar , Consenso , Técnica Delfos , Diagnóstico Diferencial , Febre/complicações , Humanos , Linfadenite/complicações , Faringite/complicações , Estomatite Aftosa/complicações , Inquéritos e Questionários , Síndrome
6.
Orphanet J Rare Dis ; 12(1): 167, 2017 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-29047407

RESUMO

BACKGROUND: Hereditary recurrent fevers (HRF) are a group of rare monogenic diseases leading to recurrent inflammatory flares. A large number of variants has been described for the four genes associated with the best known HRF, namely MEFV, NLRP3, MVK, TNFRSF1A. The Infevers database ( http://fmf.igh.cnrs.fr/ISSAID/infevers ) is a large international registry collecting variants reported in these genes. However, no genotype-phenotype associations are provided, but only the clinical phenotype of the first patient(s) described for each mutation. The aim of this study is to develop a registry of genotype-phenotype associations observed in patients with HRF, enrolled and validated in the Eurofever registry. RESULTS: Genotype-phenotype associations observed in all the patients with HRF enrolled in the Eurofever registry were retrospectively analyzed. For autosomal dominant diseases (CAPS and TRAPS), all mutations were individually analyzed. For autosomal recessive diseases (FMF and MKD), homozygous and heterozygous combinations were described. Mean age of onset, disease course (recurrent or chronic), mean duration of fever episodes, clinical manifestations associated with fever episodes, atypical manifestations, complications and response to treatment were also studied. Data observed in 751 patients (346 FMF, 133 CAPS, 114 MKD, 158 TRAPS) included in the Eurofever registry and validated by experts were summarized in Tables. A total of 149 variants were described: 46 TNFRSF1A and 27 NLRP3 variants, as well as various combinations of 48 MVK and 28 MEFV variants were available. CONCLUSIONS: We provide a potentially useful tool for physicians dealing with HRF, namely a registry of genotype-phenotype associations for patients enrolled in the Eurofever registry. This tool is complementary to the Infevers database and will be available at the Eurofever and Infevers websites.


Assuntos
Estudos de Associação Genética , Doenças Hereditárias Autoinflamatórias/epidemiologia , Doenças Hereditárias Autoinflamatórias/genética , Sistema de Registros , Bases de Dados Genéticas , Europa (Continente)/epidemiologia , Humanos , Estudos Retrospectivos
7.
Orphanet J Rare Dis ; 11(1): 167, 2016 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-27927236

RESUMO

INTRODUCTION: The Chronic Infantile Neurological Cutaneous and Articular (CINCA, or Neonatal-onset multisystem inflammatory disease NOMID) is a rare autoinflammatory disease identified in 1987 by Prieur et al., typically characterized by the triad of skin rash, arthropathy and central nervous system manifestations. It represents the most severe phenotype of the cryopyrin-associated periodic syndrome (CAPS). CLINICAL DESCRIPTION AND ETIOLOGY: The syndrome is due to autosomal dominant gain of function mutations in NLRP3, which encodes a key component of the innate immunity that regulates the activation and secretion of interleukin (IL)-1ß. From the first days of life, patients display an urticarial rash in association with chronic inflammation with a typical facies featured by frontal bossing and saddle back nose. The CNS manifestations include chronic aseptic meningitis leading to brain atrophy, mental delay and sensorineural hearing loss. Chronic polyarthritis and alteration of the growth cartilage also may be present. CINCA/NOMID diagnosis is made clinically, based on the presence of characteristic features. The detection of NLRP3 mutations is diagnostic in 65-70% of cases. Indeed, up to 40% of affected patients are negative for germline NLRP3 mutations and several subjects are carriers of somatic mosaicism. Due to the pivotal role of Cryopyrin in the control of Caspase-1 activation and the massive secretion of active IL-1ß observed in cryopyrin-mutated individuals, anti-IL1 treatment represents the standard therapy. CONCLUSION: Prognosis of CINCA/NOMID syndrome has been changed by the availability of anti-IL1 drugs. Nowadays, the use of anti-IL-1 drugs has sensibly reduced the risk of developing main complications such as severe intellectual disability, hearing-loss and amyloidosis, if treatment is started early on.


Assuntos
Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/patologia , Humanos , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
8.
Ann Rheum Dis ; 75(8): 1550-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26386126

RESUMO

OBJECTIVES: Systemic auto-inflammatory disorders (SAIDs) are a heterogeneous group of monogenic diseases sharing a primary dysfunction of the innate immune system. More than 50% of patients with SAID does not show any mutation at gene(s) tested because of lack of precise clinical classification criteria and/or incomplete gene screening. To improve the molecular diagnosis and genotype interpretation of SAIDs, we undertook the development of a next-generation sequencing (NGS)-based protocol designed to simultaneous screening of 10 genes. METHODS: Fifty patients with SAID, already genotyped for the respective causative gene(s), were massively sequenced for the coding portions of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12, NOD2, PSTPIP1, IL1RN, LPIN2 and PSMB8. Three different bioinformatic pipelines (Ion Reporter, CLC Bio Genomics Workbench, GATK-based in-house workflow) were compared. RESULTS: Once resulting variants were compared with the expected mutation list, no workflow turned out to be able to detect all the 79 variants known in the 50 DNAs. Additional variants were also detected, validated by Sanger sequencing and compared to assess true and false positive detection rates of the three workflows. Finally, the overall clinical picture of 34 patients was re-evaluated in the light of the new mutations found. CONCLUSIONS: The present gene panel has resulted suitable for molecular diagnosis of SAIDs. Moreover, genotype-phenotype correlation has confirmed that the interpretation of NGS data in patients with an undefined inflammatory phenotype is remarkably difficult, thus supporting the need of evidence-based and validated clinical criteria to be used concurrently with the genetic analysis for the final diagnosis and classification of patients with SAIDs.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Biologia Computacional/métodos , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Frequência do Gene , Genótipo , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Mutação , Fenótipo
9.
Proc Natl Acad Sci U S A ; 112(43): 13372-7, 2015 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-26464512

RESUMO

In plants, small groups of pluripotent stem cells called axillary meristems are required for the formation of the branches and flowers that eventually establish shoot architecture and drive reproductive success. To ensure the proper formation of new axillary meristems, the specification of boundary regions is required for coordinating their development. We have identified two maize genes, BARREN INFLORESCENCE1 and BARREN INFLORESCENCE4 (BIF1 and BIF4), that regulate the early steps required for inflorescence formation. BIF1 and BIF4 encode AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) proteins, which are key components of the auxin hormone signaling pathway that is essential for organogenesis. Here we show that BIF1 and BIF4 are integral to auxin signaling modules that dynamically regulate the expression of BARREN STALK1 (BA1), a basic helix-loop-helix (bHLH) transcriptional regulator necessary for axillary meristem formation that shows a striking boundary expression pattern. These findings suggest that auxin signaling directly controls boundary domains during axillary meristem formation and define a fundamental mechanism that regulates inflorescence architecture in one of the most widely grown crop species.


Assuntos
Flores/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação da Expressão Gênica de Plantas/fisiologia , Ácidos Indolacéticos/metabolismo , Meristema/metabolismo , Transdução de Sinais/fisiologia , Zea mays/crescimento & desenvolvimento , Teorema de Bayes , Clonagem Molecular , Biologia Computacional , Primers do DNA/genética , Ensaio de Desvio de Mobilidade Eletroforética , Flores/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica de Plantas/genética , Hibridização In Situ , Meristema/crescimento & desenvolvimento , Modelos Genéticos , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
10.
Ann Rheum Dis ; 74(5): 799-805, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25637003

RESUMO

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Sistema de Registros , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/classificação , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Medicina Baseada em Evidências , Febre Familiar do Mediterrâneo/classificação , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Febre , Doenças Hereditárias Autoinflamatórias/classificação , Humanos , Lactente , Masculino , Deficiência de Mevalonato Quinase/classificação , Deficiência de Mevalonato Quinase/diagnóstico , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Adulto Jovem
11.
Best Pract Res Clin Rheumatol ; 28(2): 263-76, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24974062

RESUMO

Autoinflammatory diseases are characterized by the presence of chronic or recurrent systemic inflammation secondary to abnormal activation of innate immunity pathways. Many of these diseases have been found to have mutations in the genes within these pathways. Due to their rarity, non-specific symptoms and the very recent genetic and phenotypic identification and recognition, a delay in diagnosis is common. Nevertheless, some specific clinical features should help the clinician to make the diagnosis. The purpose of this article is to provide a brief clinical description of these conditions and to present clinical flow-charts useful for a correct diagnosis of children with suspected autoinflammatory syndromes.


Assuntos
Artrite/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Imunidade Inata/fisiologia , Artrite/complicações , Artrite/imunologia , Criança , Doença Crônica , Diagnóstico Diferencial , Febre/etiologia , Doenças Hereditárias Autoinflamatórias/complicações , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Mutação , Síndrome
12.
Front Immunol ; 4: 351, 2013 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-24198817

RESUMO

Inherited autoinflammatory diseases are secondary to mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to seemingly unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed new lights on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of an autoinflammatory disease. The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways responsible for the activation and secretion of the potent inflammatory cytokine interleukin-1ß (IL-1ß). It became clear that several multi-factorial inflammatory conditions display a number of pathogenic and clinical similarities with inherited autoinflammatory diseases. The dramatic effect of interleukin-1 (IL-1) blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders. Several IL-1 blockers are now available on the market. In this review we outline the more recent novelties in the treatment with different IL-1 blockers in inherited and multi-factorial autoinflammatory diseases.

13.
Clin Exp Rheumatol ; 31(3 Suppl 77): 118-26, 2013 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24064025

RESUMO

In this paper we provide a critical digest of the recent literature on inherited autoinflammatory diseases. We reviewed all the articles published during the last 24 months on monogenic autoinflammatory diseases and selected the most relevant studies regarding the pathogenesis, clinical aspects and management of these conditions. In particular, we focused the attention on the more frequent conditions, familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS) and TNF-receptor associated periodic syndrome (TRAPS).


Assuntos
Doenças Hereditárias Autoinflamatórias , Animais , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/imunologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Febre , Predisposição Genética para Doença , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Imunossupressores/uso terapêutico , Fenótipo , Prognóstico , Fatores de Risco
14.
Autoimmun Rev ; 12(1): 81-6, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22884553

RESUMO

PURPOSE OF THE REVIEW: Inherited autoinflammatory syndromes are conditions caused by mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to an uncontrolled inflammation. The understanding of the molecular pathways involved in these disorders has shed a new light on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. In this review we give a start of the art of the use of biologics in these disorders. MAIN TOPICS: The dramatic response to anti IL-1 drugs in cryopyrin-associated periodic syndromes represents the brightest example of the possibility to completely dampen inflammation in these severe disorders with the selective blockade of a single pivotal cytokine. Periodic fevers are characterized by recurrent episodes of fever, usually treated with on demand steroids. However the increasing frequency of fever episodes or the development of a chronic disease course may require a continuous long-term treatment, with anti-TNF or IL-1 blockers in mevalonate kinase deficiency and TNF-receptor associated periodic syndrome. Anti-IL-1 treatment is also effective in FMF patients resistant or partially responsive to colchicine. The deficiency of the interleukin-1-receptor antagonist (DIRA) is caused by mutations in the gene encoding for the interleukin-1 receptor antagonist (IL-1Ra). In this case t he recombinant IL-1Ra (anakinra) is the treatment of choice. Due to their extreme rarity the response to the available biologic drugs in other autoinflammatory diseases is still largely anecdotal.


Assuntos
Fatores Biológicos/uso terapêutico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Humanos , Interleucina-1beta/antagonistas & inibidores
15.
Swiss Med Wkly ; 142: w13602, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22714396

RESUMO

The monogenic autoinflammatory syndromes are conditions caused by mutations of genes coding for proteins that play a pivotal role in the regulation of the inflammatory response. Due to their genetic nature, most of these disorders have an early onset. Clinically they are characterised by recurrent flares of systemic inflammation presenting most of the time as sudden fever episodes associated with elevation of acute phase reactants and with a number of clinical manifestations such as rash, serositis, lymphadenopathy and arthritis. Symptom-free intervals are characterised by complete wellbeing, normal growth and complete normalisation of acute phase reactants. Familial Mediterranean fever (FMF), mevalonate-kinase deficiency (MKD) and tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) are the three monogenic disorders subsumed under the term periodic fevers, while a systemic inflammation dominated by a characteristic urticarial rash associated with a number of other clinical manifestations is typical of familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous and articular syndrome (CINCA). These diseases represent the clinical spectrum of different mutations of a gene named cold-induced autoinflammatory syndrome 1 (CIAS-1, or NLRP3) coding for a protein called cryopyrin. Hence these disorders are also known as cryopyrin-associated periodic syndromes (CAPS). Other conditions are characterised by typical granulomatous formations (granulomatous disorders). Blau's syndrome (familial juvenile systemic granulomatosis) presents with non-caseating granulomatous inflammation affecting the joint, skin, and uveal tract (the triad of arthritis, dermatitis and uveitis) and is associated with mutations of the NACHT domain of the gene CARD15 (or NOD2).


Assuntos
Doença Granulomatosa Crônica/genética , Doenças Hereditárias Autoinflamatórias/genética , Doença Granulomatosa Crônica/fisiopatologia , Doença Granulomatosa Crônica/terapia , Doenças Hereditárias Autoinflamatórias/fisiopatologia , Doenças Hereditárias Autoinflamatórias/terapia , Humanos , Inflamação/genética
16.
Ann Rheum Dis ; 71(12): 1961-5, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22580583

RESUMO

OBJECTIVE: To evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever. METHODS: 113 children carrying MEFV mutations (44 with mutations in two alleles, 69 heterozygous) and 205 children negative for mutations in genes associated with periodic fevers were analysed. The following groups of patients were considered: patients carrying two high penetrance mutations (M694V, M694I, M680I); one high, one low penetrance mutation; two low penetrance mutations; one high penetrance mutation; one low penetrance mutation; genetically negative patients. RESULTS: Patients with two MEFV mutations displayed a shorter duration of fever attacks and higher prevalence of a positive family history than patients carrying one MEFV mutation and genetically negative patients. Severe abdominal pain, chest pain and pleurisy were also more frequent in patients with two MEFV mutations compared with children with one MEFV mutation and genetically negative patients. Conversely, a higher frequency of exudative and erythematous pharyngitis, enlargement of cervical lymph nodes, aphthous stomatitis and non-specific skin rash was observed in genetically negative patients and, to a lesser extent, in patients with one MEFV mutation. The frequency of 'familial Mediterranean fever (FMF)-like symptoms' decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with an opposite trend for 'periodic fever, aphthous stomatitis, pharyngitis, adenitis-like symptoms'. CONCLUSIONS: This clinical observation supports recent findings contrasting the notion of FMF being a pure autosomal recessive disorder associated with recurrence of mutations leading to loss of protein function. A dosage effect could be invoked, giving rise to symptom onset even in the presence of one wild-type allele.


Assuntos
Proteínas do Citoesqueleto/genética , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Febre Familiar do Mediterrâneo/etnologia , Febre Familiar do Mediterrâneo/genética , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Éxons/genética , Feminino , Dosagem de Genes/genética , Genes Recessivos/genética , Humanos , Lactente , Masculino , Penetrância , Fenótipo , Prevalência , Pirina
17.
PLoS One ; 6(5): e20014, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21637346

RESUMO

BACKGROUND: T helper 17 cells (T(H)-17) represent a lineage of effector T cells critical in host defence and autoimmunity. In both mouse and human IL-1ß has been indicated as a key cytokine for the commitment to T(H)-17 cells. Cryopyrin-associated periodic syndromes (CAPS) are a group of inflammatory diseases associated with mutations of the NLRP3 gene encoding the inflammasome component cryopyrin. In this work we asked whether the deregulated secretion of IL-1ß secondary to mutations characterizing these patients could affect the IL-23/IL-17 axis. METHODOLOGY/PRINCIPAL FINDINGS: A total of 11 CAPS, 26 systemic onset juvenile idiopathic arthritis (SoJIA) patients and 20 healthy controls were analyzed. Serum levels of IL-17 and IL-6 serum were assessed by ELISA assay. Frequency of T(H)17 cells was quantified upon staphylococcus enterotoxin B (SEB) stimulation. Secretion of IL-1ß, IL-23 and IL-6 by monocyte derived dendritic cells (MoDCs), were quantified by ELISA assay. A total of 8 CAPS and 11 SoJIA patients were also analysed before and after treatment with IL-1ß blockade. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of T(H)17 compared to control subjects. On the contrary, SoJIA patients displayed a frequency of T(H)17 similar to normal donors, but were found to have significantly increased serum level of IL-6 when compared to CAPS patients or healthy donors. Remarkably, decreased IL-17 serum levels and T(H)17 frequency were observed in CAPS patients following in vivo IL-1ß blockade. On the same line, MoDCs from CAPS patients exhibited enhanced secretion of IL-1ß and IL-23 upon TLRs stimulation, with a reduction after anti-IL-1 treatment. CONCLUSION/SIGNIFICANCE: These findings further support the central role of IL-1ß in the differentiation of T(H)17 in human inflammatory conditions.


Assuntos
Proteínas de Transporte/genética , Interleucina-1beta/metabolismo , Mutação/genética , Células Th17/citologia , Adolescente , Adulto , Artrite Juvenil/sangue , Artrite Juvenil/genética , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/sangue , Síndromes Periódicas Associadas à Criopirina/genética , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Humanos , Memória Imunológica , Lactente , Interferon gama/metabolismo , Interleucina-17/sangue , Subunidade p19 da Interleucina-23/metabolismo , Interleucina-6/sangue , Contagem de Linfócitos , Masculino , Monócitos/citologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fenótipo , Receptores CCR6/metabolismo , Células Th17/metabolismo , Adulto Jovem
18.
Curr Opin Rheumatol ; 22(5): 579-84, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20657282

RESUMO

PURPOSE OF REVIEW: Periodic fever, apthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is the most common cause of periodic fever of unknown origin in childhood. During the last years a number of studies on large series of patients have shed more light on the actual clinical characterization, long-term outcome and response to treatment. Current PFAPA criteria have low specificity since they are positive in a considerable proportion of patients with inherited periodic fevers. We report on the findings coming from the analysis of large cohorts of PFAPA patients and the possible implication for the differential diagnosis. An update on the efficacy of possible prophylactic treatments and tonsillectomy is given. RECENT FINDINGS: A diagnostic score developed in a large series of children identifies patients meeting PFAPA criteria and at higher risk to carry relevant mutations of genes associated with periodic fevers. Randomized studies on the efficacy of tonsillectomy give a more evidence-based justification to this possible therapeutic approach. SUMMARY: The findings coming from the recent literature give new information to clinicians for the correct diagnostic approach to pediatric and adult patients presenting periodic fever of unknown origin and provide an updated overview on the therapeutic possibilities for patients presenting a persistence of fever attacks.


Assuntos
Febre de Causa Desconhecida/diagnóstico , Linfadenite/diagnóstico , Faringite/diagnóstico , Corticosteroides/uso terapêutico , Diagnóstico Diferencial , Febre de Causa Desconhecida/tratamento farmacológico , Humanos , Linfadenite/tratamento farmacológico , Faringite/tratamento farmacológico , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/tratamento farmacológico , Síndrome , Resultado do Tratamento
19.
Arthritis Rheum ; 60(11): 3476-84, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19877056

RESUMO

OBJECTIVE: Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1beta or tumor necrosis factor alpha (TNFalpha). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor-associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-kappaB signaling, both of which are processes that influence the development of inflammatory cells. METHODS: The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. RESULTS: Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23-3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNFalpha. CONCLUSION: These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function.


Assuntos
Febre Familiar do Mediterrâneo/genética , Predisposição Genética para Doença/genética , Monócitos/metabolismo , Mutação de Sentido Incorreto/genética , Polimorfismo Genético/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Estudos de Casos e Controles , Caspases/metabolismo , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/metabolismo , Febre Familiar do Mediterrâneo/metabolismo , Feminino , Homozigoto , Humanos , Masculino , Deficiência de Mevalonato Quinase/genética , Deficiência de Mevalonato Quinase/metabolismo , Monócitos/patologia , NF-kappa B/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
20.
Pediatrics ; 124(4): e721-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19786432

RESUMO

OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.


Assuntos
Febre Familiar do Mediterrâneo/genética , Linfadenite/genética , Faringite/genética , Estomatite Aftosa/genética , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Febre de Causa Desconhecida/diagnóstico , Febre de Causa Desconhecida/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Linfadenite/diagnóstico , Masculino , Mutação , Faringite/diagnóstico , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores do Fator de Necrose Tumoral/genética , Estomatite Aftosa/diagnóstico , Síndrome
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