Clinical Characteristics and Treatment of Blau Syndrome in Chinese Children-a National Multicenter Study / 罕见病研究

  Objective  To study the demographic and clinical characteristics, correlation of genotype and phenotype and treatment of Blau syndrome to facilitate early diagnosis and timely treatment of Blau syndrome.  Methods  Seventy-two patients with Blau syndrome from 11 centers from May 2006 to April 2022 were retrospectively analyzed, and their general information, clinical data, laboratory examination and treatment medication were collected.  Results  The distribution of patients with Blau syndrome was uniform in geographical north and south of China, and there was no obvious gender bias. The mean age of onset was (14.30±12.81) months, and the age of diagnosis was (55.18±36.22) months. 35% of patients with Blau syndrome happened before 1 year old, and all patients developed before 5 years old. 87.50% (63/72) had granulomatous arthritis, 65.28% (47/72) had rash, 36.11% (26/72) had ocular involvement, 27.78% (20/72) had fever, and 15.28% (11/72) had pulmonary involvement. Arthritic manifestations of Blau syndrome were most at risk, followed by rash, ocular involvement, and fever.The first 25 months of the disease, the risk of developing a rash was the greatest. The risk of developing arthritis was the greatest between 25 months and 84 months. The main mutations were p.R334Q and p.R334W, and patients with p.R334Q mutation had relatively high incidence of fever (35.71%[5/14] vs. 14.29%[1/7], P=0.43) and ocular involvement (42.86%[6/14]vs. 28.57%[2/7], P=0.51). There was a relatively high incidence of rash (85.71%[6/7] vs. 64.29%[9/14], P=0.59) in patients with the p.R334W mutation. Forty-five patients(62.50%)were treated with a combina-tion of glucocorticoid and methotrexate. Twenty-two patients were treated with tumor necrosis factor antagonist in addition to glucocorticoid and methotrexate.  Conclusions  The risk of different clinical manifestations of Blau syndrome from high to low was arthritis, followed by rash, ocular involvement and fever. The main treatment was glucocorticoid combined with methotrexate, to which biological agents could be added.

Efficacy of Ezetimibe tablets in the treatment of sitosterolemia with thrombocytopenia / 中华实用儿科临床杂志

The clinical features and genetic variants of the patient with sitosterolemia who was referred to Shanghai Children′s Medical Center, Shanghai Jiaotong University School of Medicine from June 2019 to January 2020 were retrospectively analyzed.The patient was treated with Ezetimibe tablets combined with diet control, and the follow-up was performed regularly.Besides, a relevant literature review was conducted.A 7-year and 5-month-old boy was referred to the hospital for " repeated thrombocytopenia for 7 months" with normal serum cholesterol.The whole exome sequencing showed that compound heterozygous mutations (p.Arg446*, p.Gln251*) in ABCG5 gene were inherited from their parents respectively.Hence, he was diagnosed with sitosterolemia.After 29 days of treatment with Ezetimibe tablets combined with diet control, the patient′s platelets returned to normal values without obvious adverse reactions related to drugs.Children with sitosterolemia may present with rare thrombocytopenia, and the therapeutic effects of Ezetimibe tablets combined with diet control are favorable.

Role of adaptive immune cells in the pathogenesis of juvenile idiopathic arthritis / 国际儿科学杂志

Juvenile idiopathic arthritis(JIA)is a common chronic rheumatic disease in childhood.It is not a single disease, but a group of heterogeneous diseases including different subtypes.The etiology and pathogenesis of JIA are still unclear.It is currently believed that immune response disorders play an important role in its pathogenesis and development.Different subgroups of adaptive immune cells(including T lymphocytes and B lymphocytes, etc.)may participate in the pathogenesis of different subtypes of JIA, leading to different clinical manifestations.However, the specific mechanism of action and related molecular signaling pathways have not been fully elucidated.This paper reviews the latest research results in recent years and explores the role of different types of adaptive immune cells in the development of various subtypes of JIA, which will help the precise diagnosis and individualized treatment of each subtype of JIA.

Clinical characteristics and early recognition of thrombotic microangiopathy in children with systemic lupus erythematosus / 中国小儿急救医学

Objective:To analyze the clinical characteristics of children diagnosed with systemic lupus erythematosus(SLE)complicated with thrombotic microangiopathy(TMA)for early recognition.Methods:We retrospectively reviewed the clinical records of 14 SLE patients with TMA hospitalized at Shanghai Children′s Medical Center, Shanghai Jiaotong University School of Medicine from December 2005 to October 2020.Results:The incidence of TMA was 5.65%(14/248)of the hospitalized patients with SLE and 7.87%(14/178)of the hospitalized patients with lupus nephritis.Four patients were boys while ten patients were girls.One boy was six years old and other 13 patients were from 11 to 18 years old.Their SLEDAI scores ranged from 14 to 31, and all of them were severe activity.Renal biopsy of 11 patients during TMA course all revealed lupus nephritis(type Ⅳ, n=8; type Ⅳ+ Ⅴ, n=3). These 14 SLE children were diagnosed with TMA within 3 days to 2 months after admission.At the beginning of the hospitalization, only six patients had both anemia and thrombocytopenia, while eight patients only had moderate anemia.All of the patients had obvious hypocomplementemia.Especially in the patients with first onset of SLE without treatment, their serum levels of C3 were less than 0.17 g/L and C4 were less than 0.07 g/L.Moreover, glomerular filtration rates of these patients were lower than that in normal range.The follow-up time were 0.2-11.3 years(median time was 2.6 years). After treatment, six patients obtained complete remission, and five patients obtained partial remission.One patient had sudden death during the 4th plasmapheresis, and the other two patients deteriorated. Conclusion:Children with SLE and TMA are mostly in severe disease activity, and renal pathology is type Ⅳ lupus nephritis.The SLE children with anemia should be paid special attention to the level of serum complement whether they have thrombocytopenia or not.If the level of serum complements decrease obviously, glomerular filtration rates should be monitored closely and schistocytes should be searched repeatedly in the blood smears of the peripheral blood to facilitate the early recognition of TMA.

Progress in the diagnosis and treatment of connective tissue disease-associated interstitial lung disease in children / 国际儿科学杂志

There is a wide spectrum of rheumatic diseases which manifest in children′s connective tissue disease(CTD). Lung involvement is common within the spectrum of CTD.And interstitial lung disease (ILD) is among the most serious complications.The early diagnosis and treatment is vital to improve the prognosis.In this article, the mechanisms, subtypes, clinical manifestations and management of children′s CTD-ILD are reviewed.

Macrophage activation syndrome in a newborn of adult-onset Still's disease mother: a case report and literature review / 中国新生儿科杂志

Objective To study the clinical characteristics of neonatal macrophage activation syndrome (MAS) associated with maternal rheumatic diseases and improve the understanding of neonatal MAS.Method Clinical data of MAS in a newborn infant with adult-onset Still's disease (AOSD) mother was retrospectively studied.From the establishment day of databases (CNKI,VIP,Wanfang,Pubmed and Embase) to December 2017,literature were retrieved with key words including "newborn","macrophage activation syndrome" and "hemophagocytic lymphohistiocytosis (HLH) ".Clinical features of infant MAS/HLH with maternal rheumatic diseases were summarized.Result A 27-day-old boy with AOSD mother manifested with fever,watery stools,irritability,prominent enlargement of right parotid gland and right cervical lymphadenitis.The infant was diagnosed with MAS due to coagulopathy,multiple organ dysfunction,hypofibrinogenemia and increased levels of ferritin.Anti-SSA/Ro52kD and stool rotavims antigen were positive.The infant recovered with intravenous immunoglobulin and steroids therapy.Follow-up at 2-year-old were normal.A total of 3 other cases of neonatal MAS/HLH were retrieved.All patients had high fever,hepatosplenomegaly and multiple organ dysfunction,impaired digestive system (abdominal distention,diarrhea and ascites),disseminated intravascular coagulation (2 cases),mental disorders (1 case),complete atrioventricular block (1 case) and severe hypotension (1 case).Laboratory results showed thrombocytopenia,elevated level of hepatic enzyme and serum ferritin in all patients.Targeted panel-based next generation sequencing were all negative for pathogenic gene mutations.After treatments of steroids,intravenous immunoglobulin and chemotherapy,all patients improved and ultimately cured.Conclusion In view of the impacts of the maternal rheumatic diseases on fetus,newborns with early onset high fever and hepatosplenomegaly should be suspected of MAS.Early diagnosis and effective treatment are crucial for clinical improvement.

Childhood primary Sjogren syndrome with central nervous system symptoms as the first manifestation: a case report and literature review / 临床儿科杂志

Objective To explore the diagnosis and treatment of childhood primary Sjogren syndrome (pSS) with central nervous system symptoms as the first manifestation. Methods The clinical data of an 11-year-old male with pSS which had onset with fever and headache was retrospectively analyzed. The related literatures were reviewed. Results The subject was diagnosed with pSS by autoantibody detection, lip biopsy, and ophthalmologic examination. The symptoms were improved after immunosuppressive therapy. According to the literature, the incidence of childhood pSS was low, in which the incidence with involvment of the nervous system as primanry manifestation was even lower, and headache is the most common symptom of central nervous system. The application of corticosteroids and immunosuppressants may help improve the conditions. Conclusions Involvement of central nervous system in childhood pSS is not typical. Detection of autoantibodies and lip biopsy are helpful for diagnosis.

Childhood primary Sjogren syndrome with central nervous system symptoms as the first manifestation: a case report and literature review / 临床儿科杂志

Objective To explore the diagnosis and treatment of childhood primary Sjogren syndrome (pSS) with central nervous system symptoms as the first manifestation. Methods The clinical data of an 11-year-old male with pSS which had onset with fever and headache was retrospectively analyzed. The related literatures were reviewed. Results The subject was diagnosed with pSS by autoantibody detection, lip biopsy, and ophthalmologic examination. The symptoms were improved after immunosuppressive therapy. According to the literature, the incidence of childhood pSS was low, in which the incidence with involvment of the nervous system as primanry manifestation was even lower, and headache is the most common symptom of central nervous system. The application of corticosteroids and immunosuppressants may help improve the conditions. Conclusions Involvement of central nervous system in childhood pSS is not typical. Detection of autoantibodies and lip biopsy are helpful for diagnosis.

Expression and purification of recombinant human Cosmc extracellular domain in Sf-9 insect cells / 中国免疫学杂志

Objective:In the present study,Bac-to-Bac baculovirus expression system was used to obtain recombinant human Cosmc extracellular domain protein,which can lay the foundation for the research about the structure and function of Cosmc protein in vitro,and simultaneously provide ideas for the research of O-glycosylation and related diseases. Methods: The Cosmc extracellular domain ( Cosmc-ED) gene was cloned into a transfer vector pFastBac1 to form the recombinant donor plasmid pFastBac1-Cosmc ED, which was transformed into competent cells DH10Bac. By using blue-white selection and PCR analysis,we could obtain recombinant shuttle vector rBacmid-Cosmc ED. Then, the recombinant gene DNA of rBacmid-Cosmc ED was used to transfect Sf-9 mediated by cationic lipid formulation,and the recombinant baculovirus bacmid was obtained,which was further used to infect the serum-free cell Sf-9 to express Cosmc-ED in the supernatant. Then the protein of interest was detected by SDS-PAGE and Western blot and purified with Ni-NTA affinity column. Results:SDS-PAGE and Western blot analysis showed a specific band about 33 kD,consistent with the interest protein. Mass spectrometry results further prove that the protein was Cosmc extracellular domain protein. Conclusion: Human Cosmc-ED protein can be successfully expressed in Sf-9 insect cells and laid basis for subsequent studies.

The serum levels of galactose-deficient IgA1 in children with Henoch-Sch?nlein purpura and its clinical significance / 临床儿科杂志

Objective To explore the association of galactose-deifcient IgA1 levels with clinical features, and further to provide guidance for individualized treatment of HSP. Methods According to the clinical symptoms and curative effect, 57 children with HSP were divided into four groups:non-HSPN group (n=26), HSPN group (n=7), refractory HSP group (n=7) and remission group (n=17). In non-HSPN group, 12 cases received glucorticoid therapy and 14 cases did not. Serum galactose-de-ifcient IgA1 (Gd-IgA1) concentrations were detected using a Helix aspersa-lectin-based enzyme-linked immunosorbent assay (ELISA), and the total IgA1 levels were measured by ELISA. Results The serum Gd-IgA1 level was signiifcantly higher in 40 HSP children who were not cured than that in remission group and control group (P0.05). Compared with the control group, the serum Gd-IgA1 level was signiifcantly higher in HSPN group, non-HSPN group and refractory HSP, and children with refractory HSP had signiifcantly higher Gd-IgA1 level than children in non-HSPN group (P0.05). Furthermore, in non-HSPN group, the serum Gd-IgA1 level in HSP children who were not treated with glucorticoid was signiifcantly higher than that in HSP children treated with glucorticoid (P<0.05). Conclusions The serum Gd-IgA1 level is associated with the disease activ-ity and curative effect of HSP, especially in children with refractory HSP, and it is thus likely to be a new non-invasive disease activity marker for guiding the proper usage of glucocorticoid and immunosuppressants in HSP children.

Diagnostic value of serum ferritin in systemic onset juvenile idiopathic arthritis / 中华风湿病学杂志

Objective To investigate the diagnostic value of serum ferritin in children with systemic onset juvenile idiopathic arthritis (SO-JIA). Methods Fifty-seven patients with fever of unknown origin (rectal temperature>38.5 ℃ ) over two weeks and hospitalized in our general medicine ward longer than one week were enrolled in this study. Patients were recorded the course of fever, elinieal symptoms and signs including rash and swollen joints/arthralgia, laboratory tests including complete blood cell count, C-reactive protein, erythroeyte sedimentation rate, lactate dehydrogenase and the level of serum ferritin. SPSS 10.0 was used for statistical analysis. Results Two of 57 patients could not be diagnosed before discharge. The other 55 patients whose diagnosis was confirmed were divided into four groups. Twenty-five patients were SO-JIA,12 patients had hematologic or oncological diseases, 12 patients had infectious diseases and 6 patients had other rheumatic diseases. The level of serum ferritin was significantly higher (P<0.01) in SO-JIA group than in other groups. Moreover, the levels of serum ferritin in SO-JIA group were all higher than normal and the levels of serum ferritin in 76% of SO-JIA group were more than five-fold elevation. Four cut-off levels of serum ferritin level for the diagnosis of SO-JIA were selected based on clinical practice and ROC curve. When the cut-off levels of serum ferritin were 328.25, 529.50, 731.05 ng/ml and 1121.10 ng/ml, the sensitivity for the diagnosis were 100%, 88%, 72%, and 64% respectively, the specificity were 77%, 87%, 90% and 100%,respectively. Conclusion Serum ferritin is valuable for the diagnosis of SO-JIA and 529.50 ng/ml may be a good cut-off level

Influence of SNPs within interlukin-10 promoter region on the expression of interlukin-10 mRNA among childhood systemic lupus erythematosus / 中华风湿病学杂志

Objective To explore the influence of three SNPs within interlukinc (IL) 10 promoter region on the expression of interlukin 10 mRNA in childhood systemic lupus erythematosus (SLE),then to determine if the SNPs do associate with the pathogenesis of childhood SLE.Methods The levels of IL 10 mRNA were detected in children with SLE and their parents by Taqman PCR,then the correlations between levels of IL 10 mRNA and haplotypes were assessed.Results The results showed that haplotype GCC was associated with higher level of IL 10 mRNA within children with SLE.Conclusion Haplotype GCC is associated with high secretion of IL 10 within childhood SLE,but not operate independently,and maybe it regulates the high secretion of IL 10 with other susceptible genes of SLE.

Association of SNPs within IL-10 promoter region with childhood systemic lupus erythematosus / 中华风湿病学杂志

Objective To explore the association between three SNPs of IL 10 promoter and childhood systemic lupus erythematosus (SLE).Methods Three SNPs( 1082/ 819/ 592) were genotypes,and evidence for linkage disequilibrium was analyzed using Genehunter 2 0 software.The correlations between symptoms and haplotypes were assessed.Results The results showed that all genotypes and haplotypes in the IL 10 promoter region exhibited to significant association with childhood SLE,and no significant differences in clinical features among childhood SLE with various haplotypes could be demonstrated.But the frequence of haplotype GCC ( 1082 *G 819 *C 592 *C) in children with SLE and their parents was higher than that in adult SLE patients and adult normal controls,and the frequence of ATA in children with SLE was lower than that of adult SLE patients.Conclusion It is concluded that haplotype GCC might have certain relationship with childhood SLE,which deserves further study.