RESUMO
ROSAH syndrome was recently identified as an autosomal dominant systemic disorder due to mutations in ALPK1. It was characterized by retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. We collected and summarized the clinical data of two patients with juvenile onset splenomegaly and oculopathy. Whole exome sequencing (WES) was adapted for genetic analysis. Mutations in ALPK1 were confirmed by Sanger sequencing. Besides juvenile oculopathy and splenomegaly, both patients had intermittent fever and anhidrosis. Patient 2 also experienced recurrent upper respiratory infections in her infancy and developed dental and nail problems in childhood. Elevated TNF-α was their prominent laboratory features. Both patients were found to have a previously reported mutation, c.710C>T, p. T237M (NM_001102406) in ALPK1. Anti-TNF treatment of adalimumab was applied to patient 1, after which her optic disc edema in the left eye continued and the visual acuity deteriorated further. Patient 1 underwent elective splenectomy due to concern for spontaneous rupture of the spleen. Up to date, 18 patients of ROSAH syndrome have been reported. The clinical manifestations were relatively homogeneous, prominently presenting with juvenile onset oculopathy and splenomegaly. As it mainly involves ocular fundus, severe oculopathy deeply affects the quality of life and prognosis of ROSAH patients. Now little has been known about its treatment. As a newly recognized inherited systemic disorder, ROSAH syndrome needs to be paid more attention to, especially for those with juvenile onset splenomegaly and oculopathy.
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Oftalmopatias Hereditárias/genética , Mutação/genética , Nervo Óptico/patologia , Proteínas Quinases/genética , Adolescente , Criança , Edema , Feminino , Humanos , NF-kappa B/metabolismo , Linhagem , Distrofias Retinianas , Transdução de Sinais , Esplenomegalia , Síndrome , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima , Sequenciamento do ExomaRESUMO
BACKGROUND: Several complications like calcinosis, interstitial lung disease (ILD) or malignancy, are primary causes leading to poor outcomes in idiopathic inflammatory myopathies (IIM) patients. Specific antibodies might help to indicate the occurrence or absence of these complications. OBJECTIVE: The aim of this study was to evaluate the association of anti-nuclear matrix protein 2 antibody (anti-NXP2) with calcinosis, ILD and malignancy in IIM patients. METHODS: Two investigators independently searched literature about the relation of anti-NXP2 with calcinosis, ILD, malignancy in IIM patients in PubMed, EMBASE, Web of Science databases, then selected eligible articles and extracted data from the included studies. The association between anti-NXP2 and these complications was assessed by odds ratios (OR) and 95% confidence intervals (95% CI). Further quantitative meta-analysis, subgroup analysis, sensitivity analysis and publication bias analysis were conducted with STATA 14.0 software (Stata Corp.; College Station, Texas, USA). A fixed-effects model (the Mantel-Haenszel method) was employed when I2â¯<â¯25%, otherwise a random-effects model (the Mantel-Haenszel method) was used. RESULTS: Twenty cohorts with 3064 IIM patients were included in this meta-analysis, among which 9 were about calcinosis in adults, 6 about calcinosis in juvenile patients, 9 about ILD in adults, 3 about ILD in juvenile patients, while 13 about malignancy in adult patients. Anti-NXP2 was more common in patients with calcinosis than those without calcinosis (pooled ORâ¯=â¯4.00, 95% CI: 2.65-6.06 in adults; pooled ORâ¯=â¯1.62, 95% CI: 1.14-2.30 in juvenile patients). On the contrary, this antibody was less common in adult patients with ILD than those without ILD (pooled OR: 0.33, 95% CI: 0.19-0.56). No significant difference concerning the incidence of anti-NXP2 antibody was found in IIM patients between those with and without cancer (pooled ORâ¯=â¯1.42, 95% CI: 0.69-2.91). CONCLUSION: The present study indicates that anti-NXP2 autoantibody is a risk factor for development into calcinosis both in adult and juvenile patients, while a protective factor for ILD in adult patients. Anti-NXP2 had no relation with malignancy in adult patients.
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Adenosina Trifosfatases/imunologia , Autoanticorpos/imunologia , Proteínas de Ligação a DNA/imunologia , Miosite/imunologia , Calcinose/etiologia , Humanos , Doenças Pulmonares Intersticiais/imunologia , Miosite/complicações , Viés de PublicaçãoAssuntos
Subpopulações de Linfócitos/citologia , Adolescente , Criança , Pré-Escolar , China , Humanos , Lactente , Recém-Nascido , Contagem de Linfócitos , Valores de ReferênciaRESUMO
OBJECTIVES: We aimed to determine the prevalence of cardiovascular involvement in our Blau syndrome (BS) cohort and provide detailed analysis of their cardiovascular manifestations and outcome. We also tried to find out the risk factors for developing cardiovascular involvement. METHODS: Clinical manifestations, laboratory findings, and treatments were reviewed. Clinical features were compared between children with cardiovascular involvement and those without angiocardiopathy. RESULTS: A total of 38 BS children were eligible for final analysis. Among them, 13 (34.2%) developed Takayasu-like vasculitis and/or cardiopathy. Compared with those without angiocardiopathy, recurrent fever was more frequent in BS patients with cardiovascular involvement (p < 0.001). What is more, tumor necrosis factor alpha antagonists (anti-TNF) were more urgently needed in children with cardiovascular involvement (p = 0.015). BS patients with cardiovascular involvement include 4 with Takayasu-like vasculitis and 9 with cardiopathy. The onset of cardiovascular manifestations ranged from 0.75 to 18.5 years of age, with most cases occurring before school period. Symptoms were elusive and lacked specificity, such as dizziness, short of breath, and edema. Some patients were even identified because of the unexpected hypertension during follow-up. Cardiopathy and vasculitis occurred in patients with different genotypes. Imaging changes were discovered before the presentation of the typical triad in 3/4 patients with Takayasu-like vasculitis. Three children developed left ventricular dysfunction with decreased left ventricular ejection fraction. Combination of glucocorticoids and methotrexate with anti-TNF agents is a common treatment option for these BS patients. In the cohort, BS-related cardiovascular involvement was controlled well, with cardiac structural and functional abnormalities completely recovered and slower progression of vasculitis lesions. CONCLUSION: Cardiovascular manifestations is not rare in BS patients. Because of its insidious onset, a systematic and comprehensive assessment of cardiovascular involvement should be performed in newly diagnosed patients with BS. Aggressive initiation of anti-TNF agents may be beneficial to improve the prognosis. Key Points ⢠About 34.2% patients with Blau syndrome developed Takayasu-like vasculitis and/or cardiopathy. ⢠Compared with those without angiocardiopathy, recurrent fever and application of anti-TNF agents were more frequent in BS patients with cardiovascular involvement (p < 0.001, p = 0.015) ⢠Regular assessment of cardiovascular involvement is extremely necessary because of its insidious onset.
Assuntos
Artrite , Cardiopatias , Sarcoidose , Sinovite , Arterite de Takayasu , Uveíte , Vasculite , Criança , Humanos , Inibidores do Fator de Necrose Tumoral , Volume Sistólico , Função Ventricular Esquerda , Fenótipo , Arterite de Takayasu/complicações , Arterite de Takayasu/tratamento farmacológico , Arterite de Takayasu/diagnósticoRESUMO
BACKGROUND: Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs. METHODS: This was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses. RESULTS: A total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions. CONCLUSION: The largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.
Assuntos
Síndromes Periódicas Associadas à Criopirina , Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Humanos , Criança , Talidomida/efeitos adversos , Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Febre Familiar do Mediterrâneo/tratamento farmacológicoRESUMO
BACKGROUND: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype-phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype-phenotype analysis of Chinese PPRD patients. METHODS: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis. RESULTS: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R2 = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027). CONCLUSIONS: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities.
Assuntos
População do Leste Asiático , Artropatias , Humanos , População do Leste Asiático/genética , Genótipo , Mutação , Fenótipo , Estudos Retrospectivos , Artropatias/congênito , Artropatias/genéticaRESUMO
Blau syndrome (BS) is a monogenic autoinflammatory disease caused by mutations in nucleotide-binding oligomerization domain containing 2 (NOD2). BS is characterized by the clinical triad of granulomatous dermatitis, arthritis and recurrent uveitis. Due to the low incidence of BS and the lack of treatment studies with large samples, a specific treatment scheme has not been established. We report the case of a patient with BS that was uncontrollable with various immunosuppressive therapies but had a good response to thalidomide. She had the typical triad of rash, arthritis and uveitis. Gene sequencing indicated a NOD2 heterozygous missense variant (c.1759C > T, p.R587C), which has been reported as a pathogenic mutation. The BS diagnosis was confirmed. After treatment with methotrexate, an anti-tumour necrosis factor (TNF)-α inhibitor and corticosteroids, the patient's clinical symptoms and inflammatory indicators remained uncontrolled, and she experienced multiple side effects, such as hypertension and growth retardation attributed to prolonged corticosteroid use. After treatment with thalidomide, her condition was controlled without recurrence or side effects, and corticosteroids were stopped as soon as possible. This report suggests that thalidomide may be effective for BS treatment, but more research is needed to evaluate its long-term efficacy and side effects.
Assuntos
Artrite , Uveíte , Artrite/diagnóstico , Artrite/tratamento farmacológico , Artrite/genética , Feminino , Humanos , Proteína Adaptadora de Sinalização NOD2/genética , Sarcoidose , Sinovite , Talidomida/uso terapêutico , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Uveíte/genéticaRESUMO
BACKGROUND: NLRP3-associated autoinflammatory disease (NLRP3-AID), caused by mutations of NLRP3, is one of the autoinflammatory diseases affecting inflammasomes. Since there are little cases of Chinese NLRP3-AID, we reported 14 Chinese NLRP3-AID patients in our center and summarized the clinical features of all Chinese patients by reviewing the literature. RESULTS: Fourteen patients had been diagnosed as NLRP3-AID in our center. 12 different NLRP3 variants were identified, among which one is novel: p.Leu361Trp. Rash, recurrent fever, arthritis/arthralgia, uveitis, sensorineural deafness, symptoms of central neural systems (CNS), and increased inflammatory markers (including CRP, ESR, except Ferritin) were the common findings in Chinese patients. The frequencies of fever, neurological symptoms, musculoskeletal manifestations and ocular manifestations in Chinese patients might differ from that of patients from other regions. Besides, we also found clubbing fingers and optic neuritis in some NLRP3-AID patients, which were not commonly mentioned in previous reports. CONCLUSION: In our study, we expanded the clinical spectrum as well as the genetic pathogenic variants of NLRP3-AID. We also found that there were some differences between Chinese patients and patients from other regions, and that Chinese patients were more likely to develop severe symptoms.
Assuntos
Doenças Hereditárias Autoinflamatórias , Proteína 3 que Contém Domínio de Pirina da Família NLR , Povo Asiático/genética , Febre , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Inflamassomos/genética , Mutação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genéticaRESUMO
Objective: This study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD). Methods: A total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR. Results: Three patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25-4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p < 0.05). The erythrocyte sedimentation rate normalized in 2 patients with AGS. The interferon score (IS) was remarkably decreased in 2 patients with SPENCD (p < 0.01). Catch-ups with growth and weight gain were observed in 3 and 2 patients, respectively. Lung lesions improved in 1 patient with SAVI and remained stable in 3 patients. Lymphopenia was found in 3 patients during the treatment without severe infections. Conclusion: The JAK inhibitors baricitinib and tofacitinib are promising therapeutic agents for patients with SAVI, AGS, and SPENCD, especially for the improvement of cutaneous lesions and febrile attacks. However, further cohort studies are needed to assess the efficacy and safety.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Inibidores de Janus Quinases , Malformações do Sistema Nervoso , Doenças Vasculares , Antivirais/uso terapêutico , Doenças Autoimunes , Doenças Autoimunes do Sistema Nervoso/genética , Humanos , Síndromes de Imunodeficiência , Interferons/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Malformações do Sistema Nervoso/tratamento farmacológico , OsteocondrodisplasiasRESUMO
BACKGROUND: We analyze the clinical manifestations and 5 years of follow-up outcomes of children with lupus nephritis (LN) and provide a reference for clinicians. METHODS: The clinical data of children diagnosed with LN (n=62) from January 2012-2015 were collected and analyzed. RESULTS: The median age at the diagnosis was 12.0 years. The female to male ratio was 3.4:1. The most prevalent clinical features were mucocutaneous involvement and hematological involvement. Renal biopsy was performed on 38 patients. Class IV and class V were the most common findings. The lupus activity was improved markedly after 3 months treatment. The rate of survival was 98.3% in 5 years. The most common side effects of corticosteroid and other immunosuppressive agent drug treatment were corticosteroid-related hypertension and high intraocular pressure. The rate of cataracts, osteoporotic fracture, and visual field defects increased as the treatment progressed. Especially, the incidence of visual field defects in children is higher than adults. CONCLUSIONS: The LN children showed a good prognosis. During the follow-up process, the adverse drug reactions, such as hormone-related hypertension and ocular hypertension, especially the visual field defects caused by hydroxychloroquine, cannot be excluded. However, multicenter long term follow-up studies are essential to substantiate the current data.
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Corticosteroides/efeitos adversos , Imunossupressores , Nefrite Lúpica , Criança , Feminino , Seguimentos , Humanos , Imunossupressores/efeitos adversos , Nefrite Lúpica/tratamento farmacológico , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease caused by mutations in the ADA2 gene. Few Chinese cases have been reported. We describe and compare the clinical features, genotypes, and treatments of Chinese DADA2 patients and non-Chinese patients. METHODS: Primary immunodeficiency disease panel or whole-exome sequencing was performed for suspected cases, and assays for adenosine deaminase 2 (ADA2) enzyme activity were also carried out for the patients and their parents. Case reports of Chinese and non-Chinese patients with DADA2 were searched in PubMed and Chinese national databases. RESULTS: Seven unrelated children from China with DADA2 were included in our study. Five were identified at Peking Union Medical College Hospital, and two had been reported previously (1 on PubMed and 1 in Chinese literature). Fourteen mutations in ADA2 were identified, 7 of which have not previously been reported in non-Chinese patients. Four children who underwent enzymatic analysis had lower ADA2 activity compared with their parents. Phenotypic manifestations included fever, skin symptoms, vasculitis, and neurologic involvement. Treatments varying from steroids, immunosuppressants, and tocilizumab, anti-TNF therapy and hematopoietic stem cell transplantation (HSCT) were effective depending on phenotype and severity. CONCLUSION: This study includes the largest number of Chinese DADA2 patients to date. We recommend the combination of enzymatic analysis with gene screening to confirm the diagnosis. Different genotypes were observed among Chinese DADA2 patients; most phenotypes were similar to those of non-Chinese DADA2 patients, except for growth retardation. Disease remission might not be achieved with anti-IL-6 therapy.
Assuntos
Adenosina Desaminase/deficiência , Inflamação/diagnóstico , Inflamação/terapia , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Adolescente , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , MasculinoRESUMO
Purpose: To identify pathogenic gene variants in the NOD2 gene and assess the clinical features of a cohort of Chinese patients affected with Blau syndrome.Methods: Eight patients from seven unrelated families were enrolled. Detailed ophthalmological examinations were performed. Sanger sequencing was used to analyze the NOD2 gene.Results: The onset age of ocular manifestations varied from 2 to 24 years (median: 5.5 years). Best corrected visual acuity (BCVA) ranged from light perception (LP) to 1.0. One patient presented with recurrent anterior uveitis, six patients had panuveitis and one patient was at the phthisis bulbi stage. One novel disease-associated variant (c.2006A>G, p.His669Arg) and four previously reported disease-causing variants (c.1000C>T, p.Arg334Trp; c.1001G>A, p.Arg334Gln; c.1442G>A, p.Gly481Asp; c.1759C>T, p.Arg587Cys) in the NOD2 gene (NM_022162.1) were identified.Conclusions: Blau syndrome is a rare autosomal dominant multisystem disease caused by a NOD2 gene defect. Recurrent anterior uveitis and/or panuveitis are the characteristic ocular findings.
Assuntos
Artrite/complicações , Oftalmopatias/etiologia , Sarcoidose/complicações , Sinovite/complicações , Uveíte/complicações , Adolescente , Adulto , Artrite/diagnóstico , Artrite/genética , Criança , Pré-Escolar , China/epidemiologia , DNA/genética , Análise Mutacional de DNA , Oftalmopatias/diagnóstico , Oftalmopatias/epidemiologia , Feminino , Testes Genéticos/métodos , Humanos , Incidência , Masculino , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , Linhagem , Fenótipo , Sarcoidose/diagnóstico , Sarcoidose/genética , Sinovite/diagnóstico , Sinovite/genética , Uveíte/diagnóstico , Uveíte/genética , Adulto JovemRESUMO
BACKGROUND: The nucleotide-binding oligomerization domain-like receptor protein 12 (NLRP12)-autoinflammatory disorder (NLRP12-AD) is a rare autoinflammatory disease characterized by recurrent fever, rash as well as musculoskeletal symptoms, which is rarely reported in Asian populations. METHODS: Three cases of NLRP12-AD presented to our hospital were studied after parental consents were obtained. Clinical presentations were recorded on a standardized case report form. Mutations of NLRP12 were detected by primary immunodeficiency disease panels and further examined by Sanger sequencing. PubMed literature search for relevant studies of systemic autoinflammatory disorders, especially NLRP12-AD between January, 2000 and January, 2019 was carried and the clinical data were summarized. Comparisons were made between groups in terms of onset age and of ethnicity. RESULTS: All our patients presented with fever, rash and arthritis/arthralgia, and sensorineural as well as sensorineural deafness (1/3), uveitis (1/3), abdominal pain (1/3), and myalgia (1/3). Two novel mutation variations, p.W581X and p.L558R, are reported here. In addition, we also found that two patients inherited the mutated alleles from their healthy parents, and this may be evidence of haploinsufficiency. CONCLUSIONS: Although the genotypes are similar, the clinical manifestations between Chinese patients and Western patients vary thus highlighting the possible influence of ethnic and environmental factors. On the other hand, some genetic mutations may lead to specific phenotype, as we have found a high prevalence of sensorineural hearing loss among p.R284X patients.
Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Pré-Escolar , China , Feminino , Genótipo , Humanos , Lactente , FenótipoRESUMO
Objective: Monogenic autoinflammatory diseases (AIDs) are inborn disorders caused by innate immunity dysregulation and characterized by robust autoinflammation. We aimed to present the phenotypes and genotypes of Chinese pediatric monogenic AID patients. Methods: A total of 288 pediatric patients clinically suspected to have monogenic AIDs at the Department of Pediatrics of Peking Union Medical College Hospital between November 2008 and May 2019 were genotyped by Sanger sequencing, and/or gene panel sequencing and/or whole exome sequencing. Final definite diagnoses were made when the phenotypes and genotypes were mutually verified. Results: Of the 288 patients, 79 (27.4%) were diagnosed with 18 kinds of monogenic AIDs, including 33 patients with inflammasomopathies, 38 patients with non-inflammasome related conditions, and eight patients with type 1 interferonopathies. Main clinical features were skin disorders (76%), musculoskeletal problems (66%), fever (62%), growth retardation (33%), gastrointestinal tract abnormalities (25%), central nervous system abnormalities (15%), eye disorders (16%), ear problems (9%), and cardiopulmonary disorders (8%). The causative genes were ACP5, ADA2, ADAR1, IFIH1, LPIN2, MEFV, MVK, NLRC4, NLRP3, NLRP12, NOD2, PLCG2, PSMB8, PSTPIP1, TMEM173, TNFAIP3, TNFRSF1A, and TREX1. Conclusions: The present study summarized both clinical and genetic characteristics of 18 kinds of monogenic AIDs found in the largest pediatric AID center over the past decade, with fever, skin problems, and musculoskeletal system disorders being the most prevalent clinical features. Many of the mutations were newly discovered. This is by far the first and largest monogenic AID report in Chinese pediatric population and also a catalog of the phenotypic and genotypic features among these patients.
Assuntos
Genótipo , Doenças Hereditárias Autoinflamatórias/genética , Imunidade Inata/genética , Mutação , Fenótipo , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Feminino , Genes , Doenças Hereditárias Autoinflamatórias/sangue , Doenças Hereditárias Autoinflamatórias/epidemiologia , Humanos , Lactente , Recém-Nascido , Inflamassomos/genética , Masculino , Sequenciamento do ExomaRESUMO
BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) has many clinical features overlapping with familial Mediterranean fever (FMF), which is caused by mutations in MEFV gene. And FMF patients were easily misdiagnosed as sJIA in China. So we speculate that MEFV is critical genetic background for sJIA and influences patients' severity. In this study, we aim to figure out whether MEFV mutations are risk factor for the occurrence of sJIA and to study the association of MEFV mutations with disease severity of sJIA patients. METHODS: The present study includes 57 sJIA children and 2573 healthy controls. Odd ratio with 95% confidence interval based on allelic frequency of MEFV mutations or variants was used to evaluate their contribution to sJIA susceptibility. Meta-analysis was then performed to reach comprehensive conclusion. All included sJIA patients were grouped by presence and number of MEFV mutations. Clinical data and indicators of disease severity were compared among different groups. Multiple linear regression method was used to find out whether the number of MEFV variants is associated with the severity of sJIA. Kaplan-Meier curves and log rank test were used to estimate the probability of the first relapse. RESULTS: The MEFV mutations of our subjects predominantly existed in exons 2 and 3. No significant difference was found in allelic frequency between sJIA children and healthy controls. Meta-analysis demonstrated that p.M694V/I was a risk factor for sJIA (pooled OR: 7.13, 95% CI: 3.01-16.89). The relative period of activity was significantly lower in the one mutation group than those with more than one mutation (p = 0.0194). However, no relevance was found in multiple linear regression models. CONCLUSIONS: The mutation p.M694V/I in MEFV might be a risk factor for sJIA. SJIA patients carrying more than one heterozygous mutation in MEFV tend to be more severe than those containing only one, but studies in other cohort of patients need to be performed to validate it.
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Artrite Juvenil/genética , Pirina/genética , Artrite Juvenil/fisiopatologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Exantema/fisiopatologia , Éxons/genética , Feminino , Febre/fisiopatologia , Predisposição Genética para Doença , Hepatomegalia/fisiopatologia , Humanos , Lactente , Estimativa de Kaplan-Meier , Modelos Lineares , Síndrome de Ativação Macrofágica/fisiopatologia , Masculino , Mutação , Razão de Chances , Recidiva , Serosite/fisiopatologia , Esplenomegalia/fisiopatologiaRESUMO
BACKGROUND: Systemic-onset juvenile idiopathic arthritis (SoJIA) is one of most serious subtypes of juvenile idiopathic arthritis. Although the pathogenesis of SoJIA remains unclear, several studies have suggested a correlation between gut dysbiosis and JIA. Further understanding of the intestinal microbiome may help to establish alternative ways to treat, or even prevent, the disease. AIM: To explore alterations in fecal microbiota profiles in SoJIA patients and to evaluate the correlations between microbiota and clinical parameters. METHODS: We conducted an observational single-center study at the Pediatric Department of Peking Union Medical College Hospital. Children who were diagnosed with SoJIA at our institution and followed for a minimum period of six months after diagnosis were recruited for the study. Healthy children were recruited as a control group (HS group) during the same period. Clinical data and stool samples were collected from SoJIA patients when they visited the hospital. RESULTS: The SoJIA group included 17 active and 15 inactive consecutively recruited children; the control group consisted of 32 children. Firmicutes and Bacteroidetes were the two most abundant phyla among the total sample of SoJIA children and controls. There was a significant difference among the three groups in observed species, which was the highest in the Active-SoJIA group, followed by the Inactive-SoJIA group and then HS group (Active-SoJIA vs HS: P = 0.000; and Inactive-SoJIA vs HS: P = 0.005). We observed a lower Firmicutes/Bacteroidetes ratio in SoJIA patients (3.28 ± 4.47 in Active-SoJIA, 5.36 ± 8.39 in Inactive-SoJIA, and 5.67 ± 3.92 in HS). We also observed decreased abundances of Ruminococcaceae (14.9% in Active-SoJIA, 17.3% in Inactive-SoJIA, and 22.8% in HS; Active-SoJIA vs HS: P = 0.005) and Faecalibacterium (5.1% in Active-SoJIA, 9.9% in Inactive-SoJIA, and 13.0% in HS; Active-SoJIA vs HS: P = 0.000) in SoJIA compared with HS. By contrast, the abundance of Bacteroidaceae was the highest in the Active-SoJIA group, followed by the Inactive-SoJIA and HS groups (16.5% in Active-SoJIA, 12.8% in Inactive-SoJIA, and 9.7% in HS; Active-SoJIA vs HS: P = 0.03). The Spearman correlation analysis revealed a negative correlation between Proteobacteria or Enterobacteriaceae and juvenile arthritis disease activity score on 27 joints (JADAS-27). CONCLUSION: The composition of the intestinal microbiota is different in SoJIA patients compared with healthy children. The dysbiosis presents partial restoration in inactive status patients.
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BACKGROUND: Primary immunodeficiency diseases (PIDs) patients may show systemic lupus erythematosus (SLE)-like autoimmunity disorders, such as cytopenias, as well as polyarthritis, which leads to concerns of misdiagnosis. We diagnosed three RALD cases between 2015 and 2018, who were suspected as SLE and summarized clinical characteristics. METHODS: We collected and analyzed the clinical data of the 3 cases. DNA was extracted from the patients' and their parents' peripheral blood as well as oral mucosa cells, hair follicles, and nails. Genes were detected with the application of gene trapping high-throughput sequencing using PIDs panel and suspicious gene or mutation was further verified by Sanger sequencing. RESULTS: 1. CLINICAL FEATURES: On the one hand, the patients presented with severe thrombocytopenia, facial erythema, arthritis, positive autoantibodies and other manifestations, supporting the diagnosis of SLE. On the other hand, symptoms including early onset ages, recurrent infections, lymphadenopathy, hepatosplenomegaly, monocytosis and hypergammaglobulinemia, were common observed in PIDs. 2. Gene analysis: NRAS mutations (c.38G > A, p.G13D or c.37G > T, p.G13C) were found in the blood of the patients. Besides, the same set of mutations was detected in buccal mucosa of patient 1 and nails of patient 3 while the frequency was much lower. However, no mutation was found in other tissues or in their parents' blood. Consequently, they were NRAS somatic mutated RALD. CONCLUSIONS: For those early-onset SLE-like patients with predominant hematologic disorders, monocytosis, recurrent infectious history, accompanied with hepatosplenomegaly and lymphadenopathy, a genetic screening of PIDs might be required.
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Síndrome Linfoproliferativa Autoimune/diagnóstico , GTP Fosfo-Hidrolases/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Proteínas de Membrana/genética , Mutação/genética , Idade de Início , Síndrome Linfoproliferativa Autoimune/etnologia , Síndrome Linfoproliferativa Autoimune/genética , Pré-Escolar , China/etnologia , Diagnóstico Diferencial , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Lúpus Eritematoso Sistêmico/etnologia , MasculinoRESUMO
Background: Familial Mediterranean fever (FMF) is an inherited auto-inflammatory disorder and is extremely rare in Chinese. This study aimed to investigate the demographic, clinical, and genetic features of FMF in a series of Chinese pediatric patients. Methods: This was a retrospective case series of children with recurrent febrile or inflammatory episodes and referred to the Peking Union Medical College Hospital between 06/2013 and 06/2018. All suspected patients were genetically diagnosed and met the Tel-Hashomer criteria for FMF. Demographic, clinical, genetic, and treatment characteristics were collected. Descriptive statistics were used. Results: Eleven patients were included (seven boys and four girls). The median age at the time of disease onset was 7.1 (range, 3-12) years, while the median age at diagnosis was 10.9 (range, 6-15) years. The median delay in diagnosis was 2.1 years (range, 6 months to 6.7 years). Fever (100%, 11/11) was the most common symptom, followed by joint pain (63.6%, 7/11), rash (54.5%, 6/11), abdominal pain (36.4%, 4/11), and oral ulcers (18.2%, 2/11), without evidence of amyloidosis. C-reactive protein (81.8%, 9/11) and erythrocyte sedimentation (90.9%, 10/11) were increased during attacks. All patients harbored one to five different MEFV mutations, with E148Q and L110P being the most frequent. A novel non-synonymous mutation F636Y in exon 10 was discovered. Favorable responses to colchicine was observed in all six treated patients. Conclusion: The most common variants in our study were E148Q and L110P. F636Y may found for the first time. Colchicine led to favorable responses in all treated patients.
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BACKGROUND: The aim of the meta-analysis was to evaluate the association between 10 widely studied polymorphisms of interleukin-23 receptor gene (IL-23R) and ankylosing spondylitis (AS). METHODS: A comprehensive literature search, screening of eligible articles and data extraction was performed independently by two investigators. Further meta-analysis was conducted with STATA 12.0 software (Stata Corp.; College Station, TX, USA). The association between IL-23R polymorphisms and AS was evaluated by odds ratio (OR) and 95% confidence intervals (95% CI). RESULTS: Twenty-five case-control studies with 8431 cases and 8972 controls were included in this meta-analysis. Quantitative meta-analysis revealed that minor allele frequency (MAF) of rs1004819, rs1495965, and rs2201841 was significantly higher in the AS group (p value < .001, < .001, = .010, respectively). MAF of rs10489629, rs11209026, rs11465804, and rs1343151was significantly lower in the AS group (p value = .002, < .001, = .032, < .001, respectively). However, there is no significant difference between these two groups in rs10889677, rs11209032, and rs7517847 frequency (p value = .128, .237, .131, respectively). CONCLUSIONS: The present study indicates that minor allele carriers of rs1004819, rs1495965, and rs2201841 are susceptible to AS. Conversely, minor alleles of rs10489629, rs11209026, rs11465804, and rs1343151 have protective effect on AS.
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Genótipo , Receptores de Interleucina/genética , Espondilite Anquilosante/genética , Alelos , Estudos de Casos e Controles , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: The aim of the current study was to determine the contributions of several common mutations in the Mediterranean fever (MEFV) gene, namely, E148Q, M680I, M694V and V726A, to ankylosing spondylitis (AS) susceptibility. METHODS: Two investigators independently searched the literature regarding the association of MEFV with AS in the PubMed, EMBASE, Web of Science, and Scopus databases. They independently selected eligible articles and then extracted data from the included studies. The associations between MEFV mutations and AS risk were assessed with odds ratios (ORs) and 95% confidence intervals (95% CI). Further analyses were conducted with STATA 12.0 software (Stata Corp.; College Station, Texas, USA). RESULTS: Four mutations (E148Q, M680I, M694V and V726A) were genotyped in 869 AS cases and 879 controls from the 8 eligible studies. Of the four mutations, M694V (pooled OR: 3.330, 95% CI: 2.129-5.208) was found to be associated with AS through overall analysis. However, the other mutations demonstrated no relation with AS (pooled ORs: 1.295, 1.258, 1.778; 95% CI: 0.886-1.891, 0.688-2.298 and 0.938-3.371). No significant publication bias was discovered in the meta-analysis. CONCLUSIONS: The present study indicates that the MEFV M694V mutation may contribute to the pathogenesis of AS. The associations between the other mutations and AS need to be validated with more relevant and well-designed studies.