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1.
Autoimmun Rev ; 20(4): 102774, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33609798

RESUMO

Systemic autoinflammatory disorders comprise an expanding group of rare conditions. They are mediated by dysfunction of the innate immune system and share a core of phenotypic manifestations including recurrent attacks of fever, cutaneous signs, chest or abdominal pain, lymphadenopathy, vasculopathy, and musculoskeletal symptoms. Diagnosis is often established in childhood, but a growing number of adult patients are being recognized with systemic autoinflammatory disorders, including adult-onset disease. In this review, we provide a concise update on the pathophysiology, clinical presentation, and diagnostic approach of systemic autoinflammatory disorders with an emphasis on the adult patient population. Despite the recent advances in genetic testing, the diagnosis of autoinflammatory disease in adult patients is often based on a thorough knowledge of the clinical phenotype. Becoming acquainted with the clinical features of these rare disorders may assist in developing a high index of suspicion for autoinflammatory disease in patients presenting with unexplained episodes of fever or inflammation.


Assuntos
Doenças Hereditárias Autoinflamatórias , Doenças do Sistema Imunitário , Adulto , Criança , Febre , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Inflamação/diagnóstico , Doenças Raras
2.
Z Rheumatol ; 79(7): 611-623, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32761370

RESUMO

Autoinflammatory syndromes are characterized by periodic febrile attacks in combination with increased inflammatory markers. The dysregulation of different cellular signaling pathways leads to an excessive immune response, which can in turn promote multisystemic inflammatory processes. Due to overlapping symptoms, variable expressivity and pleiotropy, a purely clinical diagnosis of autoinflammatory diseases is difficult in many cases. Because an early and definitive diagnosis can greatly improve the quality of life of many patients, molecular genetic methods have become an important part of the diagnostic process. With the development of next-generation sequencing (NGS), the genetic diagnosis of patients with autoinflammatory diseases has significantly improved. Considerable progress has not only been made in the genetic characterization of undiagnosed patients, but additionally in identifying numerous new disease-associated genes; however, the plethora of molecular genetic analytical methods makes it difficult to select the method with the highest diagnostic specificity and sensitivity. The NGS technologies have also led to a large increase in the number of identified variants, making the clinical evaluation of these variants more complex. Consensus-driven and standardized molecular diagnostic guidelines, both for the diagnostic process and for the interpretation of the obtained results, have therefore become essential.


Assuntos
Doenças Hereditárias Autoinflamatórias , Qualidade de Vida , Biomarcadores , Febre , Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Síndrome
4.
Hautarzt ; 71(5): 342-358, 2020 May.
Artigo em Alemão | MEDLINE | ID: mdl-32303770

RESUMO

Systemic autoinflammatory diseases are characterized by a spontaneous chronic inflammatory reaction mediated by the innate immunity. The inflammatory processes involve many organs including the skin. Diagnosis remains a challenge despite new molecular genetic methods, but early diagnosis is crucial for the prevention of long-term complications such as amyloidosis. Skin manifestations are often observed early in the course of the disease and can be decisive in the diagnosis.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Humanos , Imunidade Inata , Inflamação , Pele
5.
Clin Chem ; 66(4): 525-536, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32176780

RESUMO

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.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/genética , Proteínas do Citoesqueleto/genética , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Adaptadora de Sinalização NOD2/genética , Guias de Prática Clínica como Assunto , Diagnóstico Pré-Natal , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
6.
Pediatr Rheumatol Online J ; 18(1): 7, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31948488

RESUMO

BACKGROUND: Serum phagocyte-derived alarmins S100A8/9 and S100A12 are considered useful for the assessment of inflammatory diseases. Our study evaluated the use of S100 proteins in a pediatric clinical setting for estimating disease activity and supporting diagnosis. METHODS: Patients (n = 136) who had S100 proteins tested as part of clinical care were included in this study and relevant information obtained from the medical record: C-reactive protein (CRP), disease activity status (inactive: = 0 joint; active: > 0 active joint), systemic symptoms in systemic JIA (sJIA), and symptoms of flare of other autoinflammatory and fever syndromes. Patients were categorized as: sJIA, non-systemic JIA (nsJIA), other defined autoinflammatory syndromes (AID) and systemic undifferentiated recurring fever syndromes (SURFS). RESULTS: Patients with sJIA (n = 21) had significantly higher levels of S100A8/9 and S100A12 compared to patients with nsJIA (n = 49), other AIDs (n = 8) or SURFS (n = 14) (all p < 0.0001). Compared to CRP [area under the receiver operating characteristics curve (AUC) = 0.7], S100 proteins were superior in differentiating sJIA from AID and SURFS [AUC = 0.9]. S100A8/9 and S100A12 levels were not associated with disease activity in nsJIA, AID or SURFS. S100A8/9 and S100A12 levels were significantly higher in active sJIA compared to inactive (p = 0.0002 and p = 0.0002 respectively). CONCLUSION: Compared to other autoinflammatory and fever syndromes, sJIA patients have markedly higher levels of S100A8/9 and S100A12 proteins which may assist with diagnosis. S100 levels slightly outperformed CRP in distinguishing sJIA from other diagnoses and in sJIA disease activity. S100 proteins may aid in monitoring disease activity in sJIA patients.


Assuntos
Artrite Juvenil/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Proteínas S100/sangue , Artrite Juvenil/sangue , Biomarcadores/sangue , Calgranulina A/sangue , Calgranulina B/sangue , Estudos Transversais , Doenças Hereditárias Autoinflamatórias/sangue , Humanos , Estudos Retrospectivos , Proteína S100A12/sangue , Sensibilidade e Especificidade , Índice de Gravidade de Doença
7.
Rheumatology (Oxford) ; 59(6): 1241-1246, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31562507

RESUMO

OBJECTIVE: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominantly inherited autoinflammatory disease caused by mutations of the TNFRSF1A gene. To address the association between TNFRSF1A mutations and clinical phenotype, we analyzed four pedigrees of TRAPS patients. METHODS: Four Greek patients with TRAPS-like clinical features were screened for TNFRSF1A mutations by sequencing exons 2, 3 and 4. Following positive testing, twenty-two members of their families were also genetically and clinically screened. RESULTS: Twenty-six members of four unrelated Greek families were investigated. The C73Y (c.305G>A) mutation of the TNFRSF1A gene was identified in five patients, with two of the five carrying a concomitant R92Q variation. We also identified seven C73W (c.306C>G), two T50M (c.236C>T) and seven R92Q (c.362G>A) carriers. Symptoms varied and the C73Y, C73W and T50M mutations were associated with the most severe clinical manifestations. The R92Q phenotype ranged from asymptomatic to mild disease. Molecular modelling linked pathogenicity with aberrant TNFRSF1A disulphide bond formation. CONCLUSION: In this first pedigree analysis of TRAPS in Greece, we identified the rare C73Y TNFRSF1A mutation. A wide clinical spectrum was observed with the C73Y, C73W and T50M mutations that affect TNFRSF1A disulphide bonds and are associated with worse symptoms.


Assuntos
Febre/diagnóstico , Predisposição Genética para Doença , Doenças Hereditárias Autoinflamatórias/diagnóstico , Mutação , Fenótipo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Análise Mutacional de DNA , Feminino , Febre/genética , Grécia , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Masculino , Modelos Moleculares , Linhagem , Índice de Gravidade de Doença
8.
Rheumatology (Oxford) ; 59(2): 344-360, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31325311

RESUMO

OBJECTIVES: The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. METHODS: We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. RESULTS: Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. CONCLUSION: Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.


Assuntos
Colchicina/uso terapêutico , Febre/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Moduladores de Tubulina/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Febre/tratamento farmacológico , Febre/genética , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Fenótipo , Recidiva , Adulto Jovem
9.
Rheumatology (Oxford) ; 58(Suppl 6): vi44-vi55, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31769854

RESUMO

Systemic autoinflammatory diseases (SAIDs) are a group of inflammatory disorders caused by dysregulation in the innate immune system that leads to enhanced immune responses. The clinical diagnosis of SAIDs can be difficult since individually these are rare diseases with considerable phenotypic overlap. Most SAIDs have a strong genetic background, but environmental and epigenetic influences can modulate the clinical phenotype. Molecular diagnosis has become essential for confirmation of clinical diagnosis. To date there are over 30 genes and a variety of modes of inheritance that have been associated with monogenic SAIDs. Mutations in the same gene can lead to very distinct phenotypes and can have different inheritance patterns. In addition, somatic mutations have been reported in several of these conditions. New genetic testing methods and databases are being developed to facilitate the molecular diagnosis of SAIDs, which is of major importance for treatment, prognosis and genetic counselling. The aim of this review is to summarize the latest advances in genetic testing for SAIDs and discuss potential obstacles that might arise during the molecular diagnosis of SAIDs.


Assuntos
Predisposição Genética para Doença , Testes Genéticos/tendências , Doenças Hereditárias Autoinflamatórias/diagnóstico , Imunidade Inata/genética , Animais , Feminino , Previsões , Testes Genéticos/métodos , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Masculino , Mutação , Doenças Raras
10.
Rheumatology (Oxford) ; 58(Suppl 6): vi31-vi43, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31769858

RESUMO

The systemic autoinflammatory diseases are disorders of the innate immune system distinguished by severe inflammation resulting from dysregulation of the innate immune system. Hereditary fever syndromes, such as FMF, TNF receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes and mevalonate kinase deficiency, were the first group of systemic autoinflammatory diseases for which a genetic basis was established, between 1999 and 2001. Currently according to the latest report of the international union of immunological societies, 37 separate monogenic disorders were classified as autoinflammatory. In addition to the abovementioned monogenic conditions, we describe Schnitzler's syndrome, a well-defined, acquired autoinflammatory condition without a clear genetic basis. For the purposes of this review, we discuss several conditions defined by the latest consensus process as systemic autoinflammatory diseases. We focus on those disorders where recent studies have contributed to further phenotypic characterization or had an impact on clinical management.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Imunidade Inata/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Síndrome de Schnitzler/diagnóstico , Feminino , Predisposição Genética para Doença , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/mortalidade , Doenças Hereditárias Autoinflamatórias/terapia , Humanos , Inflamassomos/imunologia , Masculino , Mutação , Prognóstico , Doenças Raras , Medição de Risco , Síndrome de Schnitzler/genética , Síndrome de Schnitzler/mortalidade , Síndrome de Schnitzler/terapia , Análise de Sobrevida
11.
Actas dermo-sifiliogr. (Ed. impr.) ; 110(9): 710-727, nov. 2019. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-185563

RESUMO

La piel es el órgano más extenso y más expuesto del cuerpo humano. Ello implica un magnífico terreno para el diagnóstico precoz de las enfermedades sistémicas que cursan con afectación sistémica y para las cuales la piel se vuelve un marcador diagnóstico. Las bases conceptuales y los criterios diagnósticos de muchas de estas entidades se han visto modificados o ampliados en los últimos años, con lo que la aproximación a la biopsia cutánea y la evaluación de los signos dermatopatológicos útiles en el diagnóstico precoz han variado también. En esta revisión intentamos hacer un enfoque de algunos de los procesos sistémicos con repercusión cutánea que más han variado conceptualmente en las últimas décadas


The skin is the largest and most exposed organ in the human body and the ideal place to look for signs that aid in the early diagnosis of systemic diseases with cutaneous effects. As the concepts that underpin our understanding of many of these diseases have evolved or expanded in recent years, there have also been changes in the criteria we use for early diagnosis, including our approaches to skin biopsy and dermatopathologic evaluation. This review focuses on some of the systemic processes with skin manifestations for which our basic understanding has changed most in recent decades


Assuntos
Humanos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Diagnóstico Precoce , Tela Subcutânea/patologia , Doença Relacionada a Imunoglobulina G4/patologia , Biópsia , Doenças Hereditárias Autoinflamatórias/patologia , Síndrome de Behçet/patologia , Pioderma Gangrenoso/patologia , Artrite Juvenil/complicações , Exantema , Diagnóstico Diferencial , Linfadenite Histiocítica Necrosante/complicações , Nefropatias/patologia
12.
Pediatr Rheumatol Online J ; 17(1): 70, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660995

RESUMO

BACKGROUND: Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders. CASE PRESENTATION: We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene. CONCLUSION: Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.


Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Adolescente , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colágeno Tipo VI/genética , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Febre/etiologia , Variação Genética/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cariotipagem , Masculino , Proteínas dos Microtúbulos/genética , Receptores Imunológicos/genética , Sequenciamento Completo do Genoma
13.
Lakartidningen ; 1162019 Oct 29.
Artigo em Sueco | MEDLINE | ID: mdl-31661147

RESUMO

Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is the most common autoinflammatory disorder among children in many parts of the world and an important differential diagnosis in children presenting with recurrent fever episodes. Commonly, PFAPA has an onset under the age of 5 years. Fever episodes in PFAPA usually last 3-6 days and are associated with one or more of the cardinal symptoms aphthous stomatitis, pharyngitis and cervical adenitis. The fever episodes typically recur with an interval of 3-6 weeks, often with a striking regularity. During the episodes, the patient has elevated inflammatory variables such as CRP and serum amyloid A (SAA) and may sometimes have additional symptoms such as abdominal pain, nausea and leg pain. Between the fever episodes, the patient is typically free of symptoms with normalized inflammatory variables and grows normally. Awareness and recognition of PFAPA is key to providing the patient with adequate treatment and avoiding misdiagnosis.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Biomarcadores/sangue , Pré-Escolar , Diagnóstico Diferencial , Feminino , Febre/diagnóstico , Febre/tratamento farmacológico , Febre/etiologia , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/complicações , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Humanos , Inflamação/sangue , Linfadenite/diagnóstico , Linfadenite/tratamento farmacológico , Linfadenite/etiologia , Masculino , Faringite/diagnóstico , Faringite/tratamento farmacológico , Faringite/etiologia , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/tratamento farmacológico , Estomatite Aftosa/etiologia , Síndrome
14.
Front Immunol ; 10: 1900, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474985

RESUMO

The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the MVK gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases. We have now analyzed PBMCs from an additional six patients with genetically-confirmed MKD (with different compound heterozygous MVK genotypes), and compared these with PBMCs from three healthy volunteers and four unaffected control individuals heterozygous for the commonest pathogenic variant, MVK V377I . We detected a clear accumulation of unprenylated Rab proteins, as well as unprenylated Rap1A by western blotting, in all six genetically-confirmed MKD patients compared to heterozygous controls and healthy volunteers. Furthermore, in the three subjects for whom measurements of residual mevalonate kinase activity was available, enzymatic activity inversely correlated with the extent of the defect in protein prenylation. Finally, a heterozygous MVK V377I patient presenting with autoinflammatory symptoms did not have defective prenylation, indicating a different cause of disease. These findings support the notion that the extent of loss of enzyme function caused by biallelic MVK variants determines the severity of defective protein prenylation, and the accumulation of unprenylated proteins in PBMCs may be a sensitive and consistent biomarker that could be used to aid, or help rule out, diagnosis of MKD.


Assuntos
Leucócitos Mononucleares/metabolismo , Deficiência de Mevalonato Quinase/genética , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adulto , Biomarcadores/metabolismo , Células Cultivadas , Criança , Feminino , Genótipo , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/metabolismo , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Prenilação de Proteína/genética , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismo
15.
Mol Genet Genomic Med ; 7(8): e791, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31397119

RESUMO

BACKGROUND: Somatic mosaicism is to date an uncommon finding in genetic autoinflammatory syndromes such as Cryopyrin-associated periodic syndrome, Blau syndrome, and TNF receptor-associated periodic syndrome (TRAPS). However, somatic mosaicism may be particularly important in adult-onset or atypical phenotypes of these conditions. Herein, we report a unique adult-onset TRAPS patient presenting with intermittent daily fever for 3 weeks, rash, peritonitis, and lymphadenopathy, who was found with hematopoietic mosaicism involving different white blood cell populations. METHODS: Patient's lymphocyte genomic DNA was initially analyzed by periodic fever seven-gene next-generation sequencing panel. Genomic DNAs extracted from patient's hair roots, buccal swab, and subpopulations of white blood cells were subsequently examined on the identified TNFRSF1A variant using Sanger sequencing. RESULTS: A de novo mosaic missense variant, c.265 T>C(p.Phe89Leu), in the TNFRSF1A gene was found in the patient's buccal swab, B cells, neutrophils, and NK cells but not detected in monocytes, T cells, and hair roots. CONCLUSION: These data provide additional information about somatic mosaicism in autoinflammatory conditions and provide new insights regarding cellular players that are indispensable for the phenotypic expression of TRAPS.


Assuntos
Febre/genética , Febre/fisiopatologia , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/fisiopatologia , Mosaicismo , Síndromes Periódicas Associadas à Criopirina , DNA , Febre/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfócitos , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Fatores de Necrose Tumoral/genética
16.
Acta Derm Venereol ; 99(12): 1071-1077, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408184

RESUMO

Acquired cold urticaria (ACU) is characterized by the development of itchy wheals after cold exposure. Generalized urticarial skin rashes triggered by cold exposure characterize certain monogenic autoinflammatory diseases (AIDs). The objective of this study is to investigate the presence of variants in genes causing AIDs that present with cold-induced urticarial skin rashes in patients clinically diagnosed with ACU, in order to look for susceptibility factors for the disease. Fifty patients with primary ACU were studied. Germline and post-zygotic variants on the NLRP3, NLRP12, NLRC4 and PLCG2 genes were investigated using next-generation sequencing technology. Seven patients (14%) carried 8 heterozygous germline variants in the following genes: NLRP3 (n = 1), NLRP12 (n = 3), NLRC4 (n = 1), PLCG2 (n = 3). No pathogenic or likely pathogenic variants were detected, and deep analyses of the sequences obtained did not identify any post-zygotic variant. In conclusion, ACU is not related to post-zygotic or germline pathogenic variants in the NLRP3, NLRP12, NLRC4 and PLCG2 genes.


Assuntos
Temperatura Baixa/efeitos adversos , Variação Genética , Doenças Hereditárias Autoinflamatórias/genética , Urticária/genética , Adolescente , Adulto , Idoso , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fenótipo , Fosfolipase C gama/genética , Estudos Prospectivos , Fatores de Risco , Espanha , Centros de Atenção Terciária , Urticária/diagnóstico , Urticária/imunologia , Adulto Jovem
17.
Clin Exp Immunol ; 198(3): 416-429, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31429073

RESUMO

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.


Assuntos
Febre/genética , Predisposição Genética para Doença/genética , Doenças Hereditárias Autoinflamatórias/genética , Mutação de Sentido Incorreto , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA/métodos , Feminino , Febre/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos
19.
Eur J Hum Genet ; 27(10): 1502-1508, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31186541

RESUMO

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.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Padrões de Prática Médica , Europa (Continente) , Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Humanos , Vigilância em Saúde Pública , Inquéritos e Questionários
20.
Semin Arthritis Rheum ; 49(3): 446-452, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31155445

RESUMO

OBJECTIVE: We aimed to characterize the phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases (SAIDs). METHODS: We prospectively evaluated clinical and genetic features of 92 adult patients (≥16 years) suspected of SAIDs in the period from April 2015 to October 2017, at the adult SAIDs center, Peking Union Medical College Hospital. The definite diagnosis of each disease was deemed to be present if both clinical phenotypes and genetic confirmation were met. Clinical manifestations of these patients were compared with those from the pediatric populations and patients from other countries. RESULTS: A final diagnosis of SAIDs was reached in 50 patients, including 13 familial Mediterranean fever (FMF), 10 NLRP12-associated autoinflammtory disease (NLRP12-AID), 7 NLRP3-associated autoinflammatory disease (NLRP3-AID), 5 tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), 3 Blau syndrome, 3 Yao syndrome (YAOS) and 9 periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). First disease onset during adulthood was observed in 30 patients, and the final diagnosis was delayed with a median time of 9 years. Adult monogenic SAIDs patients usually carried low-penetrance mutations and all gene variants were presented as heterozygosis or compound heterozygosis. Frequencies of clinical manifestations in Chinese adult SAIDs patients were similar with adult patients in other countries, but different from pediatric populations. CONCLUSIONS: FMF, NLRP3-AID, and NLRP12-AID are relatively common monogenic SAIDs in Chinese adults. Adult-onset SAIDs may be related to the presence of low-penetrance mutations, characterized by nonspecific, incomplete or atypical disease patterns compared with child-onset SAIDs, leading to a delay of diagnosis.


Assuntos
Autoimunidade/genética , Predisposição Genética para Doença , Doenças Hereditárias Autoinflamatórias/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , China/epidemiologia , Feminino , Seguimentos , Testes Genéticos , Genótipo , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Adulto Jovem
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