RESUMO
PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.
Assuntos
Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Humanos , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estudos de Coortes , Estudos Retrospectivos , MutaçãoRESUMO
BACKGROUND: Felty's syndrome (FS) is characterized by the triad of rheumatoid arthritis (RA), splenomegaly and neutropenia. The arthritis is typically severe and virtually always associated with high-titer rheumatoid factor. The presence of persistent neutropenia is generally required to make the diagnosis. Most patients diagnosed with FS are aged 50-70 years and have had RA for more than 10 years. It is rarely seen in patients with juvenile idiopathic arthritis (JIA), with only five cases having been reported throughout the world. CASE PRESENTATION: The present study describes the case of a 14-year-old female with a seven-year history of polyarticular JIA, presenting with splenomegaly, hepatomegaly, cholestasis and thrombocytopenia. However, she occasionally developed neutropenia. Titers of rheumatoid factor and anti-CCP were persistently high, and the antinuclear antibody titer was 1:320, while the antibody results for anti-dsDNA and anti-Sm were negative. Serum levels of IgA, IgG, IgM and IgE were all persistently elevated, and the ratio of CD19+ lymphocytes in the subgroups of lymphocytes was persistently high. The level of complements was normal. No STAT3 and STAT5B mutations were found by next-generation sequencing. The patient did not respond to methotrexate, prednisolone, hydroxychloroquine (HCQ), sulfasalazine and etanercept but was responsive to rituximab. CONCLUSIONS: JIA, thrombocytopenia and splenomegaly are the most common and important features in six children with FS, while persistent neutropenia is not seen in all these patients. No complement deficiency has been found in children with FS so far. Manifestations of FS without neutropenia may be extremely rare. There are differences between adults and children in the clinical and laboratory features of FS.
Assuntos
Artrite Juvenil , Síndrome de Felty , Adolescente , Artrite Juvenil/complicações , Síndrome de Felty/diagnóstico , Síndrome de Felty/tratamento farmacológico , Síndrome de Felty/genética , Feminino , Humanos , Neutropenia/diagnóstico , Neutropenia/etiologia , Fenótipo , Esplenomegalia/diagnóstico , Esplenomegalia/etiologia , Trombocitopenia/diagnóstico , Trombocitopenia/etiologiaRESUMO
Paediatric Behçet's disease (BD) accounts for only 2-5% of all patients with BD. Neurological and vascular involvement account for only 3.6% and 1.8% of paediatric BD in China, but both are lethal complications. We report the case of a 12-year-old Chinese boy presenting with recurrent oral ulcers, extensive thrombosis, cerebral sinus vein thrombosis and bilateral inferior pulmonary artery aneurysm. With treatment that included oral prednisone, a monthly pulse of cyclophosphamide followed by mycophenolate mofetil, and anticoagulant therapy, the patient became symptom free, his C-reactive protein and erythrocyte sedimentation rate remained normal, and the right inferior pulmonary artery aneurysm was reduced to normal. However, the left inferior pulmonary artery aneurysm progressively expanded to 64.9 mm×36.2 mm×44 mm. Eventually, the patient underwent left pulmonary aneurysm resection and a left inferior lobectomy. The post-operative maintenance treatment included oral prednisone, mycophenolate mofetil and low-dose aspirin, and the patient was followed for 2 years without recurrence. Additionally, we retrospectively analysed the clinical characteristics of 23 paediatric BD patients from our medical centre and briefly reviewed the literature on paediatric BD.
Assuntos
Aneurisma/etiologia , Síndrome de Behçet/complicações , Trombose dos Seios Intracranianos/etiologia , Criança , China , Humanos , Masculino , Artéria Pulmonar/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: The association between mutations in the TNFAIP3 gene and a new autoinflammatory disease (called A20 haploinsufficiency, HA20) has recently been recognized. Here, we describe four patients with HA20 from two unrelated Chinese families. CASE PRESENTATION: A total of four patients from two families were included. The average age at onset was 5.9 years. All patients had no signs of eye or skin problems, such as uveitis, rash, folliculitis and dermal abscess. Prior to the recognition of HA20, P1 was diagnosed with SLE, liver fibrosis and hypothyroidism. She also had no oral, genital or perineal ulcers. P2 was diagnosed with Crohn's disease and inflammatory bowel disease-related arthritis (IBD-RA). He had a perianal abscess but no oral or genital ulcers. P3, the father of P1 and P2, only had mild oral ulcers, arthralgia, and archosyrinx. P4 was diagnosed with polyarticular juvenile idiopathic arthritis (JIA), macrophage activation syndrome (MAS) and interstitial lung disease (ILD). Whole exome sequencing (WES) was performed in two families. WES revealed heterozygous c.559C > T in the TNFAIP3 gene in P1, P2 and P3, while the c.259C > T mutation in the TNFAIP3 gene was identified in P4. The c.259C > T mutations is novel. CONCLUSION: HA20 had a different phenotype between families and even between family members with the same mutation. Liver fibrosis, hypothyroidism, ILD and MAS in the patients with HA20 were first reported in this study. Our results expanded the phenotype and genotype spectrum of A20 haploinsufficiency.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença/genética , Haploinsuficiência/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Artralgia , Artrite , Artrite Juvenil , Sequência de Bases , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Hipotireoidismo , Doenças Inflamatórias Intestinais , Cirrose Hepática/patologia , Doenças Pulmonares Intersticiais , Síndrome de Ativação Macrofágica , Masculino , Mutação , Úlceras Orais , Linhagem , Fenótipo , Sequenciamento do ExomaRESUMO
RATIONALE: Gain of function (GOF) mutations in PIK3CD gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, cytomegalovirus and/or epstein-Barr virus (EBV) viremia, and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. PATIENT CONCERNS: We report a patient who was diagnosed with systemic lupus erythematosus (SLE) at a young age and was recently found to carry heterozygous mutations in PIK3CD. The patient not only presented with recurrent sinopulmonary infections, CD4 lymphopenia, lymphadenopathy, EBV viremia, and elevated serum IgM, but also met classification criteria of SLE based on persistent proteinuria and hematuria, leukopenia and anemia, low level of serum complement, and positive autoantibody for antinuclear antibodies. DIAGNOSES: Activated PI3Kδ syndrome. INTERVENTIONS: Oral prednisolone and hydroxychloroquine combined with mycophenolate mofetil was given to the patient. He was currently receiving intravenous immunoglobulin per month in association with hydroxychloroquine, low-dose prednisolone, and mycophenolate mofetil. OUTCOMES: At present, the level of complement restored to normal, hematuria and proteinuria disappeared, and liver function returned to normal. LESSONS: SLE may be a novel phenotype of GOF mutation in PI3CKD gene (GOF PIK3CD).
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação com Ganho de Função/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Lúpus Eritematoso Sistêmico/genética , Adolescente , Anticorpos Antinucleares/sangue , Povo Asiático/genética , Classe I de Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/etiologia , Infecções por Vírus Epstein-Barr/imunologia , Glucocorticoides/uso terapêutico , Herpesvirus Humano 4/imunologia , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Fenótipo , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Doenças da Imunodeficiência PrimáriaRESUMO
BACKGROUND: Henoch-Schönlein purpura (HSP) or IgA-associated vasculitis is related to immune disturbances. Polymorphisms of the heat shock protein 70-2 gene (HSP70-2) and the tumor necrosis factor-a gene (TNF-α) are known to be associated with immune diseases. The purpose of this study was to investigate the likely association of HSP70-2 (+1267A/G) and TNF-α (+308A/G) gene polymorphisms with HSP in children. METHODS: The polymerase chain reaction restriction fragment length polymorphism method was used to detect the HSP70-2 and TNF-α polymorphisms in 205 cases of children with HSP and 53 controls; and the association of these polymorphisms with HSP and HSP nephritis (HSPN) was analyzed. RESULTS: The G/G genotypic frequencies at the +1267A/G position of HSP70-2 in the HSP group (22.9%) were significantly higher than those in the healthy control group (9.4%) (χ(2)=4.764, P<0.05). The frequencies of the A/A, A/G and G/G genotypes of HSP70-2 in patients in the nephritis-free group and the HSPN group showed no statistically significant difference. The A/A genotype frequency at the +308G/A position of TNF-α in the HSP group was 8.3%, which was higher than that in the control group (χ(2)=6.447, P<0.05). The A allele frequency of TNF-α in the HSP group was higher than that in the control group, with a statistically significant difference (χ(2)=7.241, P<0.05). CONCLUSIONS: The HSP70-2 (+1267A/G) and TNF-α (+308G/A) gene polymorphisms were associated with HSP in children. The G/G homozygosity of HSP70-2 and the A/A homozygosity of TNF-α may be genetic predisposing factors for HSP.