RESUMO
BACKGROUND: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly discovered autoinflammatory condition characterised by somatic mutation of the UBA1 gene. The syndrome leads to multi-system inflammation affecting predominantly the skin, lungs and bone marrow. METHODS: We undertook a systematic review of the multisystem features and genotypes observed in VEXAS syndrome. Articles discussing VEXAS syndrome were included. Medline, Embase and Cochrane databases were searched. Information was extracted on: demographics, type and prevalence of clinical manifestations, genetic mutations and treatment. Meta-analysis using a random effects model was used to determine pooled estimates of serum markers. RESULTS: From 303 articles, 90 were included, comprising 394 patients with VEXAS. 99.2% were male, with a mean age of 67.1 years (SD 8.5) at disease onset. The most frequent diagnoses made prior to VEXAS were: relapsing polychondritis (n = 59); Sweet's syndrome (n = 24); polyarteritis nodosa (n = 11); and myelodysplastic syndrome (n = 10). Fever was reported in 270 cases (68.5%) and weight loss in 79 (20.1%). Most patients had haematological (n = 342; 86.8%), dermatological (n = 321; 81.5%), pulmonary (n = 297; 75.4%%) and musculoskeletal (n = 172; 43.7%) involvement, although other organ manifestations of varying prevalence were also recorded. The most commonly reported mutations were "c.122T > C pMET41Thr" (n = 124), "c.121A > G pMET41Val" (n = 62) and "c.121A > C pMet41Leu" (n = 52). Most patients received glucocorticoids (n = 240; 60.9%) followed by methotrexate (n = 82; 20.8%) and IL-6 inhibitors (n = 61, 15.4%). One patient underwent splenectomy; 24 received bone marrow transplants. CONCLUSION: VEXAS syndrome is a rare disorder affecting predominantly middle-aged men. This is the first systematic review to capture clinical manifestations, genetics and treatment of reported cases. Further studies are needed to optimise treatment and subsequently reduce morbidity and mortality.
Assuntos
Enzimas Ativadoras de Ubiquitina , Humanos , Masculino , Enzimas Ativadoras de Ubiquitina/genética , Feminino , Mutação , Síndrome , Idoso , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Síndrome de Sweet/genética , Síndrome de Sweet/tratamento farmacológico , Síndrome de Sweet/epidemiologia , Poliarterite Nodosa/genética , Poliarterite Nodosa/tratamento farmacológico , Poliarterite Nodosa/terapia , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/terapia , Doenças Hereditárias Autoinflamatórias/diagnósticoRESUMO
Deficiency of adenosine deaminase 2 (DADA2), caused by recessive mutations in the adenosine deaminase 2 (ADA2) gene, results in cutaneous or systemic vasculitis with variable clinical manifestations. There is only one other case in literature carrying both ADA2 and MEFV gene pathogenic variants. Here we report the second case that carries both ADA2 and MEFV pathogenic variants, presenting with characteristic phenotypes of both familial Mediterranean fever (FMF) and DADA2. A male patient, currently 29 years old, was initially diagnosed with FMF and developed livedo reticularis and nodular dermal lesions compatible with cutaneous polyarteritis nodosa (PAN) a year after diagnosis. His family history revealed a brother 2 years older than himself who was diagnosed with PAN and died at age 22 because of gut perforation secondary to acute mesenteric ischaemia. ADA2 gene mutation analysis on chromosome 22q11.1 was positive, and the patient responded to colchicine and infliximab.
Assuntos
Adenosina Desaminase , Poliarterite Nodosa , Humanos , Masculino , Adulto Jovem , Adulto , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliarterite Nodosa/complicações , Poliarterite Nodosa/diagnóstico , Poliarterite Nodosa/genética , Mutação , Fenótipo , Febre , Pirina/genéticaRESUMO
The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by loss-of-function (LOF) mutations in the ADA2 gene and was first described in 2014. Initially, it was described as vasculopathy/vasculitis that mostly affected infants and young children and closely resembled polyarteritis nodosa (PAN). Skin rash and ischemic/hemorrhagic stroke are predominant symptoms. However, the clinical spectrum of DADA2 has continued to expand since then. It has now been reported in adults as well. Besides vasculitis-related manifestations, hematological, immunological, and autoinflammatory manifestations are now well recognized. More than 100 disease-causing mutations have been described. The decrease in ADA2 enzyme leads to an increased extracellular adenosine level that, in turn, triggers a proinflammatory cascade. The disease is highly variable, and patients carrying same mutation may have different ages of presentation and clinical features. Anti-tumor necrosis factor (TNF) agents are mainstay of treatment of the vasculitis/vasculopathy phenotype. Hematopoietic stem cell transplant (HSCT) has been performed in patients with severe hematological manifestations. Recombinant ADA2 protein and gene therapy hold a promise for future.
Assuntos
Poliarterite Nodosa , Vasculite , Criança , Humanos , Pré-Escolar , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliarterite Nodosa/diagnóstico , Poliarterite Nodosa/genética , Poliarterite Nodosa/terapia , MutaçãoRESUMO
ABSTRACT: Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive monogenic autoinflammatory syndrome that is classically characterised by polyarteritis nodosa, systemic vasculitis and stroke. The spectrum of disease manifestations has broadened to encompass a range of cutaneous, vascular and haematological manifestations. We report a novel association in two sisters with heterozygous p.R169G/p.M309l mutations in ADA2 with low serum ADA2 activity who both presented similarly with clinical and histological features consistent with histiocytoid Sweet syndrome.
Assuntos
Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Síndrome de Sweet , Humanos , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Poliarterite Nodosa/genética , Síndrome de Sweet/diagnóstico , Síndrome de Sweet/genéticaRESUMO
BACKGROUND: Adenosine deaminase 2 (ADA2) deficiency is an inherited autoinflammatory syndrome caused by a defect in the ADA2 gene. Most common manifestations include peripheral vasculopathy, early-onset stroke, immunodeficiency, and haematological manifestations. Patients with pathogenic variants that are more detrimental to ADA2's enzymatic function (e.g. frameshift) have been reported to be prone to developing hematological phenotype. We report here the case of a 13-year-old Caucasian girl with a novel frameshift variant in the ADA2 gene and a clinical phenotype of early-onset stroke. CASE PRESENTATION: The patient was admitted to hospital with complaints of weakness in her right arm, unilateral facial weakness and speech problems. Her initial laboratory workup was normal; however, magnetic resonance imaging of her brain confirmed acute/subacute ischaemic changes in the posterior limb of the left-sided internal capsule and in the apical part of the thalamus. She also had manifestations of immunodeficiency - recurrent skin infections and otitis, chronic Molluscum contagiosum infection in anamnesis and B cell deficiency with a low level of serum IgA. The patient's DNA was analysed and two pathogenic variants were identified in the ADA2 gene, confirming a diagnosis of adenosine deaminase 2 (ADA2) deficiency. While one of the variants (c.506G > A (p.Arg169Gln)) has been reported previously, the other one is a novel frameshift variant, namely, c.464del (p.Pro155Hisfs*29). The patient received stroke rehabilitation, which significantly improved her functional state. Tumour necrosis factor inhibitor and methotrexate treatment was commenced, and the patient has remained stable with no further ischaemic events. CONCLUSIONS: Although rare, ADA2 deficiency should be considered in patients with early-onset stroke, especially with concomitant manifestations of inflammatory features or immunodeficiency. This case report extends the genotypic spectrum of ADA2 deficiency.
Assuntos
Síndromes de Imunodeficiência , Poliarterite Nodosa , Acidente Vascular Cerebral , Feminino , Humanos , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fenótipo , Poliarterite Nodosa/genética , MutaçãoRESUMO
Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic inflammatory disease, caused by mutations in ADA2 gene, which encodes an extracellular enzyme acting as a monocyte differentiation factor. DADA2 is first described with the clinical picture resembling polyarteritis nodosa, including livedo racemose, recurrent fever, musculoskeletal complaints. Besides, some patients have cytopenia, lymphoproliferation and mild to moderate immunodeficiency. The most crucial complication of DADA2 is neurological involvement, especially arterial stroke, which necessitates continuous treatment with anti-tumor necrosis factor α (anti-TNFα) treatment for preventing further stroke attacks. Herein, we report 5 DADA2 patients from 5 unrelated families, all had G47R mutation in at least one allele. All patients had livedo racemose, and 4 patients suffered from recurrent fever. Besides, musculoskeletal complaints and gastrointestinal symptoms were present in 4 and 3 patients, respectively. One patient had chronic arthritis and only one patient had a history of recurrent stroke without any sequela. Hematological and immunological involvement occurred in 3 and 4 patients, respectively, whereas only one had significant panhypogammaglobulinemia, requiring replacement therapy. We started etanercept treatment to all patients, which resulted the complete resolution of systemic inflammatory attacks and skin lesions and provided neurologically symptom free during their follow-up. With this report, we emphasize the importance of early referral of the patients with suspected livedo racemose to avoid the delay of DADA2 diagnosis for favorable outcome.
Assuntos
Síndromes de Imunodeficiência , Poliarterite Nodosa , Acidente Vascular Cerebral , Adenosina Desaminase/genética , Criança , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Poliarterite Nodosa/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
Adenosine deaminase 2 (ADA2) deficiency is a rare autosomal recessive disease that is caused by loss-of-function mutations in the ADA2 gene. It is considered a monogenic form of polyarteritis nodosa and frequently is positive for a type I interferon (IFN) signature. Renal manifestations in ADA2 deficiency are poorly characterized. We herein report 2 cases of ADA2 deficiency with different kidney patterns due, respectively, to a predominantly macroscopic and microscopic vasculopathy, and review the literature on kidney disease in ADA2 deficiency. Patient 1 presented with a spontaneous perirenal hematoma; angiography demonstrated multiple microaneurysms but no further defects of the renal parenchyma; his kidney function remained normal. Patient 2 experienced slowly deteriorating kidney function and proteinuria. No major angiographic abnormalities were detected, while kidney biopsy revealed massive vasculopathy resembling chronic thrombotic microangiopathy (TMA) of the small and medium-sized vessels. Both patients had a positive peripheral type I IFN signature. In immunofluorescence staining of a kidney biopsy sample from patient 2, we observed marked expression of the type I IFN-induced protein MXA within endothelial cells, especially in vessels with TMA, and in infiltrating T cells. Our findings confirm that the kidney phenotype of ADA2 deficiency results from small and medium-sized vessel vasculopathy and suggest that type I IFN may be involved in the pathogenesis of kidney lesions.
Assuntos
Interferon Tipo I , Poliarterite Nodosa , Doenças Vasculares , Humanos , Poliarterite Nodosa/genética , Adenosina Desaminase/genética , Células Endoteliais , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fenótipo , Mutação , RimRESUMO
OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease-causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA). METHODS: Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA-2 enzyme activity was assessed in selected serum samples. RESULTS: Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA-2 enzyme activity. ADA-2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA-2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2. CONCLUSION: A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA-2 testing should strongly be considered in patients with hepatitis B virus-negative idiopathic PAN.
Assuntos
Adenosina Desaminase/genética , Granulomatose com Poliangiite/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliangiite Microscópica/genética , Poliarterite Nodosa/genética , Adenosina Desaminase/deficiência , Adenosina Desaminase/metabolismo , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Pessoa de Meia-Idade , Poliarterite Nodosa/metabolismo , Análise de Sequência de DNA , Adulto JovemRESUMO
BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
Assuntos
Doenças Autoimunes/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Inflamação/genética , Mutação de Sentido Incorreto , Enzimas Ativadoras de Ubiquitina/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Citocinas/sangue , Exoma/genética , Genótipo , Arterite de Células Gigantes/genética , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Síndromes Mielodisplásicas/genética , Poliarterite Nodosa/genética , Policondrite Recidivante/genética , Análise de Sequência de DNA , Síndrome de Sweet/genética , SíndromeRESUMO
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease resulting from loss-of-function pathogenic variants in ADA2 gene, which might resemble polyarteritis nodosa (PAN). The authors present two pediatric cases of ADA2 deficiency with phenotypic manifestations of PAN, including an unusual presentation with spinal cord ischemia. Also described is an assessment of ADA2 activity and gene expression profiling with description of a previously unreported homozygous variant, c.1226C > A (p.(Pro409His)), detected in a patient with consanguineous parents, confirmed by near-absent ADA2 plasma enzymatic activity. The authors suggest to first obtain enzymatic activity, whenever DADA2 is suspected, before proceeding to genetic testing, due to its excellent cost-effective results. Moreover, physicians must be aware of this monogenic disorder, especially in the case of early-onset PAN-like manifestations, having a family member with similar manifestations or having consanguineous parents suggesting an autosomal recessive inheritance pattern. Given the multi-organ involvement, recognizing the diverse manifestations is a crucial step towards timely diagnosis and management of this potentially fatal but often treatable syndrome.
Assuntos
Adenosina Desaminase/metabolismo , Agamaglobulinemia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Poliarterite Nodosa , Imunodeficiência Combinada Severa , Adenosina Desaminase/genética , Criança , Humanos , Poliarterite Nodosa/diagnóstico , Poliarterite Nodosa/genéticaAssuntos
Adenosina Desaminase/deficiência , Doenças Hereditárias Autoinflamatórias/complicações , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Poliarterite Nodosa/diagnóstico , Adenosina Desaminase/sangue , Adenosina Desaminase/genética , Adolescente , Adulto , Biópsia , Criança , Doenças Hereditárias Autoinflamatórias/sangue , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliarterite Nodosa/sangue , Poliarterite Nodosa/genética , Poliarterite Nodosa/patologia , Estudos Retrospectivos , Pele/patologia , Adulto JovemRESUMO
Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The deficiency of adenosine deaminase 2 (DADA2) is a recently recognized autosomal recessive autoinflammatory disease, characterized by various systemic vascular and inflammatory manifestations, which is associated with ADA2 mutations. Considering that a recent screening of an international registry of children with systemic primary vasculitis revealed novel and already known variants in ADA2, this study aimed to further investigate the functional significance of the rare variants detected, namely p.Gly47Arg, p.Gly47Ala, p.Arg8Trp, p.Leu351Gln and p.Ala357Thr, by using a structural biological approach. Threedimensional models of the mutants were developed and their threedimensional (3D) structures were subjected to detailed interaction and conformational analyses. This led to suggestions that the novel mutations found may affect the formation/stability of the homodimer or may influence the activity of the enzyme. It was thus concluded that the Arg8Trp and Gly47Arg mutations affect the position and interaction of the dimerassociated HN1 helical structure and therefore, dimer formation and stabilization, while Leu351Gln and Ala357Thr influence the metal coordination in the active site. These findings shed further light onto the structural consequences of the mutations under investigation.
Assuntos
Adenosina Desaminase/química , Adenosina Desaminase/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Mutação/genética , Adenosina Desaminase/genética , Sequência de Aminoácidos , Criança , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliarterite Nodosa/genéticaAssuntos
Adenosina Desaminase/genética , Antirreumáticos/uso terapêutico , Infliximab/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Poliarterite Nodosa/tratamento farmacológico , Poliarterite Nodosa/genética , Adulto , Aspirina/análogos & derivados , Aspirina/uso terapêutico , Feminino , Humanos , Lisina/análogos & derivados , Lisina/uso terapêutico , Poliarterite Nodosa/diagnóstico , Prednisolona/uso terapêuticoRESUMO
OBJECTIVES: FMF is the most common periodic fever syndrome, characterized by recurrent episodes of fever and serosal inflammation accompanied with high acute phase reactants. The analysis of possible comorbidities is important to understand the impact of these conditions on clinical care and whether they share a common aetiological pathway. In this study, we aimed to evaluate the comorbidities associated with FMF patients in a large genetically diagnosed cohort. METHODS: We retrospectively evaluated the medical and genetic records of FMF patients who were followed up by rheumatologists in Hacettepe University for 15 years. The FMF patients who had homozygous or compound heterozygous mutations were included in the study. Comorbidities associated with FMF were divided into three groups: (i) comorbidities directly related to FMF, (ii) comorbidities due to increased innate inflammation, and (iii) comorbidities that were regarded as being incidental. RESULTS: A total of 2000 patients with a diagnosis of FMF were enrolled in the study. Among them 636 were children (31.8%) and M694V was the most common mutation in patients with associated inflammatory conditions. The frequency of AS, Iga Vasculitis (Henoch-Schönlein purpura), juvenile idiopathic arthritis, polyarteritis nodosa, multiple sclerosis and Behçet's disease were increased in patients with FMF when compared with those in the literature. CONCLUSION: This study represents the largest genetically confirmed cohort and compares the frequencies with existing national and international figures for each disease. The increased innate immune system inflammation seen in FMF may be considered as a susceptibility factor since it predisposes to certain inflammatory conditions.
Assuntos
Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Pirina/genética , Adolescente , Adulto , Amiloidose/epidemiologia , Amiloidose/genética , Artrite Juvenil/epidemiologia , Artrite Juvenil/genética , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Criança , Comorbidade , Feminino , Humanos , Vasculite por IgA/epidemiologia , Vasculite por IgA/genética , Masculino , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Mutação , Poliarterite Nodosa/epidemiologia , Poliarterite Nodosa/genética , Estudos Retrospectivos , Adulto JovemAssuntos
Anti-Inflamatórios/uso terapêutico , Etanercepte/uso terapêutico , Ácido Micofenólico/uso terapêutico , Poliarterite Nodosa/tratamento farmacológico , Poliarterite Nodosa/genética , Prednisona/uso terapêutico , Adolescente , Adulto , Criança , Progressão da Doença , Feminino , Humanos , Resultado do Tratamento , Adulto JovemAssuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico por imagem , Poliarterite Nodosa/diagnóstico por imagem , Imunodeficiência Combinada Severa/diagnóstico por imagem , Acidente Vascular Cerebral Lacunar/diagnóstico por imagem , Adenosina Desaminase/genética , Adolescente , Agamaglobulinemia/complicações , Agamaglobulinemia/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Poliarterite Nodosa/complicações , Poliarterite Nodosa/genética , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética , Pele/patologia , Acidente Vascular Cerebral Lacunar/complicações , Acidente Vascular Cerebral Lacunar/genéticaRESUMO
OBJECTIVE: Individuals with deficiency of adenosine deaminase 2 (DADA2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood-onset polyarteritis nodosa (PAN), a primary "idiopathic" systemic vasculitis. Despite similar clinical presentation, individuals with DADA2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA2. METHODS: The coding exons of ADA2 were sequenced in 60 children and adolescents with a diagnosis of PAN, cutaneous PAN, or unclassifiable vasculitis (UCV), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA2 enzyme assay and immunoblotting. RESULTS: Nine children with DADA2 (5 with PAN, 3 with UCV, and 1 with antineutrophil cytoplasmic antibody-associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely. CONCLUSION: These findings support previous observations indicating that DADA2 has extensive genotypic and phenotypic variability. Thus, screening ADA2 among children with vasculitic rash, UCV, PAN, or unexplained, early-onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA2.
Assuntos
Adenosina Desaminase/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliarterite Nodosa/genética , Adenosina Desaminase/deficiência , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Mutação , Dermatopatias Vasculares/genética , Vasculite Sistêmica/genéticaRESUMO
Deficiency of ADA2 (DADA2) is a recently described systemic inflammatory vasculopathy caused by mutations in the CERC1 gene that often, but not always, clinically resembles polyarteritis nodosa (PAN). The condition was originally characterized by livedoid rash, systemic inflammation, variable hypogammaglobulinemia, and early-onset stroke. The phenotypic spectrum has expanded to include patients with immunodeficiency syndromes and bone marrow dysfunction, which are not typical features of PAN. Exploration into the pathogenesis and treatment options of DADA2 has added to our understanding of this condition, but more studies are needed. The purpose of this article is to review the various clinical phenotypes of DADA2, and raise awareness among rheumatologists to consider DADA2 when evaluating patients presenting with PAN-like disease.
Assuntos
Adenosina Desaminase/deficiência , Imunossupressores/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Poliarterite Nodosa/diagnóstico , Poliarterite Nodosa/tratamento farmacológico , Adenosina Desaminase/genética , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/efeitos adversos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Fenótipo , Troca Plasmática , Poliarterite Nodosa/genética , Poliarterite Nodosa/imunologia , Valor Preditivo dos Testes , Resultado do TratamentoAssuntos
Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Poliarterite Nodosa/genética , Adenosina Desaminase/deficiência , Adulto , Idade de Início , Feminino , Heterozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , MutaçãoRESUMO
Polyarteritis nodosa is a systemic necrotizing vasculitis which predominantly affects medium-sized arteries. It is a rare disease nowadays. Both the nomenclature and the classification of polyarteritis nodosa was amended several times in the past. Currently, there is a distinction between the primary form described as classical polyarteritis nodosa and other forms that are associated with their probable cause e.g. with viral hepatitis B, C or HIV infection. Moreover, polyarteritis-like necrotizing vasculitis can appear in the course of genetic diseases caused by mutations in single genes. The pathogenesis of idiopathic polyarteritis nodosa is still unclear, but a dominant role of the adaptive immune system disorders is suggested. Interestingly, in the hepatitis B virus-related vasculitis development, immune complexes are believed to play a crucial role. The spectrum of clinical manifestations of polyarteritis nodosa is wide, from involving a single organ to the polyvisceral failure. In the course of polyarteritis nodosa nearly each organ can be involved, however the disease never affects the lungs. Special forms of polyarteritis nodosa include a single-organ disease and a cutaneous form. The diagnosis of polyarteritis nodosa requires integration of clinical, angiographic and biopsy findings. Recognizing the form of polyarteritis nodosa, determining affected organs and the progression of the disease is very important since those are deciding factors when choosing treatment strategies.