Purpose:This study aimed to illustrate the practical application and preliminary outcomes of a multidisciplinary team (MDT) approach in managing pediatric Fabry disease (FD), and provide a reference for the clinical management of this rare disease. Methods:This single-center, prospective, observational case series was conducted at Beijing Children's Hospital. Between March 2021 and February 2024, five pediatric patients with FD who were managed by a dedicated MDT were enrolled. The MDT operated under a model of "identification and initiation in outpatient clinics, overall management by the core team, and specialist consultation as needed." The workflow covered a dual-path diagnostic pathway (MDT-initiated or external referral), pedigree screening, baseline assessment, individualized treatment, and long-term follow-up. Results:Five pediatric FD probands were enrolled, with four diagnosed through the MDT-initiated pathway and one via external referral. For the four newly diagnosed patients, the MDT achieved a definitive diagnosis within 15-30 days of its engagement, despite a prior diagnostic odyssey of 2.0-5.9 years. Pedigree screening identified an asymptomatic sibling, enabling pre-symptomatic diagnosis. All patients commenced enzyme replacement therapy (ERT, agalsidase α) and did not develop adverse events. Through MDT coordination, they currently maintain continuous ERT at medical institutions with a travel time of 20 minutes to 2 hours. MDT-guided pain treatment, primarily with oxcarbazepine, effectively controlled neuropathic pain in most cases and improved quality of life. Psychosocial support alleviated family burdens, achieving treatment cost reimbursement rates of 60%-85%. At one-year follow-up, symptomatic improvement and significant reductions in globotriaosylsphingosine (Lyso-GL-3) levels were observed. Conclusion:The structured MDT approach facilitated accelerated diagnosis, early intervention, and comprehensive care in this pediatric FD cohort, yielding positive short-term outcomes and providing a practical reference for rare disease management.

ObjectiveA retrospective cohort study to analyze the effectiveness and safety of belimumab using in the initial treatment of childhood-onset systemic lupus erythematosus (cSLE).MethodsWe collected clinical data from all children with a first diagnosis of cSLE admitted to our center between 1 April 2021 and 1 November 2024. Patients who initiated belimumab within 1 month of diagnosis were assigned to the belimumab group, and those who did not receive belimumab comprised the control group. Propensity score matching (PSM) was applied to balance baseline characteristics between the groups. The proportion of lupus low disease activity status (LLDAS) and remission (Definitions of Remission in Systemic Lupus Erythematosus, DORIS), the disease activity scores, laboratory tests, glucocorticoid dosage, and adverse effects during the courses of treatment in two groups were analysis.ResultsThere were 39 cases in both the belimumab group and the control group. The belimumab group exhibited a higher proportion of patients achieving LLDAS (31/39 vs. 14/39, p < 0.001) and DORIS (18/39 vs. 5/39, p =0.002) compared to the control group at 12 months after treatment. Additionally, the time to achieve LLDAS and DORIS was significantly shorter in the belimumab group (log-rank p< 0.001). However, no statistical variances were observed between the two groups in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, physician global assessment (PGA) scores, complement levels, negative rates of anti-double-stranded DNA (anti-dsDNA) antibodies at each follow-up interval. From the 7th to the 12th month of treatment, the daily prednisone dose in the belimumab group was lower than in the control group. After 12 months of treatment with belimumab, B cells (p< 0.001) and immunoglobulin G (IgG) (p< 0.001) showed a significant decrease from baseline. No infusion-related adverse reactions were observed in children receiving belimumab, and the infection rate did not differ significantly from the control group.ConclusionsAdding belimumab to initial therapy facilitates quicker disease control and expedites glucocorticoid tapering in children, which can be a new treatment strategy for cSLE.

Background Recent studies suggest that oral mycophenolate mofetil (MMF) may be similar to intravenous cyclophosphamide in treating lupus nephritis. However, these therapies have not been prospectively compared in childhood-onset lupus nephritis. Methods In this prospective, multicenter, randomized trial, patients aged 5-17 years with proliferative lupus nephritis (class 3/4 +/- 5) and severely increased proteinuria (urine protein-creatinine ratio >= 1000 mg/g and/or 24-hour urinary protein excretion >25 mg/kg) were randomly assigned to receive either MMF or intravenous cyclophosphamide as initial therapy, alongside glucocorticoids. The primary end point was total renal response (TRR) at 24 weeks, with the aim of demonstrating the noninferiority of MMF compared with intravenous cyclophosphamide, using a noninferiority margin of 12%. TRR encompassed complete renal response, primary efficacy renal response, and partial renal response. Secondary end points assessed systemic disease activity and safety. Results A total of 107 patients were enrolled from 17 hospitals, with 52 assigned to the MMF group (47 completed the 24-week therapy) and 55 assigned to the cyclophosphamide group (48 completed the 24-week therapy). In the intention-to-treat population, the TRR rate was 92% in the MMF group and 89% in the cyclophosphamide group (test for noninferiority, P = 0.008). In the per-protocol population, renal response was observed in 96% of patients in the MMF group versus 94% of patients in the cyclophosphamide group (test for noninferiority, P = 0.009). The difference in TRR rate between the MMF and cyclophosphamide groups was 3% (95% confidence interval, -9% to 15%) in the intention-to-treat population and 2% (95% confidence interval, -9% to 13%) in the per-protocol population. There were no significant differences in the incidence of adverse drug reactions between the MMF and cyclophosphamide groups in the intention-to-treat population (10% versus 15%, continuity correction chi-squared test, P = 0.44). Conclusions After 24 weeks of therapy, oral MMF was noninferior to intravenous cyclophosphamide as initial therapy for childhood-onset proliferative lupus nephritis and exhibited a similar safety profile.

The total renal response rate in the mycophenolate mofetil group was found to be noninferior to that in the cyclophosphamide group. There was no significant difference in the incidence of adverse drug reactions between the mycophenolate mofetil and cyclophosphamide groups. The reduction in SLE Disease Activity Index scores was similar between the two groups. Recent studies suggest that oral mycophenolate mofetil (MMF) may be similar to intravenous cyclophosphamide in treating lupus nephritis. However, these therapies have not been prospectively compared in childhood-onset lupus nephritis. In this prospective, multicenter, randomized trial, patients aged 5–17 years with proliferative lupus nephritis (class 3/4±5) and severely increased proteinuria (urine protein-creatinine ratio ≥1000 mg/g and/or 24-hour urinary protein excretion >25 mg/kg) were randomly assigned to receive either MMF or intravenous cyclophosphamide as initial therapy, alongside glucocorticoids. The primary end point was total renal response (TRR) at 24 weeks, with the aim of demonstrating the noninferiority of MMF compared with intravenous cyclophosphamide, using a noninferiority margin of 12%. TRR encompassed complete renal response, primary efficacy renal response, and partial renal response. Secondary end points assessed systemic disease activity and safety. A total of 107 patients were enrolled from 17 hospitals, with 52 assigned to the MMF group (47 completed the 24-week therapy) and 55 assigned to the cyclophosphamide group (48 completed the 24-week therapy). In the intention-to-treat population, the TRR rate was 92% in the MMF group and 89% in the cyclophosphamide group (test for noninferiority, P = 0.008). In the per-protocol population, renal response was observed in 96% of patients in the MMF group versus 94% of patients in the cyclophosphamide group (test for noninferiority, P = 0.009). The difference in TRR rate between the MMF and cyclophosphamide groups was 3% (95% confidence interval, −9% to 15%) in the intention-to-treat population and 2% (95% confidence interval, −9% to 13%) in the per-protocol population. There were no significant differences in the incidence of adverse drug reactions between the MMF and cyclophosphamide groups in the intention-to-treat population (10% versus 15%, continuity correction chi-squared test, P = 0.44). After 24 weeks of therapy, oral MMF was noninferior to intravenous cyclophosphamide as initial therapy for childhood-onset proliferative lupus nephritis and exhibited a similar safety profile. MMF versus cyclophosphamide in the Induction Therapy of Pediatric Active Proliferative lupus nephritis, ClinicalTrials.gov, NCT05495893.

BACKGROUND:Paradoxical psoriasis (PP) is a class of adverse events associated with tumor necrosis factor α inhibitor (TNFi) that are realistically observed in the real world. We aim to quantify the signals of PP with TNFis in pediatric patients based on a pharmacovigilance study. METHODS:Data on pediatric PP cases linked to five TNFi drugs-etanercept, infliximab, adalimumab, certolizumab, and golimumab-were extracted from the FDA Adverse Event Reporting System (FAERS) database (Q1 2004 to Q1 2023). PP event reports were assessed using ROR, PRR, BCPNN, MGPS, and logistic regression to conduct a disproportionality analysis and identify signal disparities. RESULTS:The FAERS database noted 563 pediatric PP cases, with 33.69% male and 66.31% female, representing 0.58% of all pediatric TNFi adverse event reports. The average age was 14 years. Among the five TNFis, four showed disproportionate reporting of PP: etanercept [ROR = 18.53], infliximab [ROR = 17.19], adalimumab [ROR = 10.23], and certolizumab [ROR = 3.95]. CONCLUSIONS:The real-world FAERS pharmacovigilance data showed the safety signal for PP associated with TNFi in pediatric patients. Etanercept, infliximab, adalimumab, and certolizumab showed disproportionate reporting. IMPACT:This study collected and analysed the data of paradoxical psoriasis (PP) associated with TNFis in pediatric patients from a worldwide pharmacovigilance database. Reports of PP adverse events accounted for 0.58% of the overall TNFi adverse event reports in pediatric patients. Among the five TNFis, we found disproportionate reporting of PP with etanercept, infliximab, adalimumab, and certolizumab in pediatric patients.

BACKGROUND & AIM:Chronic hepatitis B (CHB) is a global public health problem affecting hundreds of millions of people and is associated with significant morbidity and mortality of liver cancer. Exosomes originate from cells and their detection in biofluids provides valuable insights into cellular and tissue alterations, thus reflecting underlying pathological states. The aim of this study was to provide exosomal RNA biomarkers of CHB and develop a machine learning model for the non-invasive diagnosis of CHB patients. METHODS:The differentially expressed genes (DEGs) were screened according to the RNA-seq data of normal and CHB liver tissues. The biomarkers were selected according to the analysis of pathway enrichment and functional annotation. The correlation of biomarkers' expression level with the inflammation stage of CHB patients was analyzed. The non-invasive diagnostic value of the potential RNA biomarkers was evaluated by checking their different expression level in the plasma exosome of healthy individuals and CHB patients. A machine learning model was constructed to diagnose CHB by combining three identified biomarkers. RESULTS:A total of 1,006 differential expressed genes (569 upregulated and 437 downregulated) were screened between normal and CHB tissues. The GO and KEGG results showed the DEGs were mainly enriched in inflammation-related pathways. Among these genes, the expression of 4 upregulated genes and 27 downregulated genes showed consistent trends with the inflammation stage utilizing an independent CHB dataset. Three (PXN-AS1, RAD9A, SLC17A9) of 27 downregulated genes were found significantly decreased in plasma exosome of CHB patients. ROC analysis revealed that PXN-AS1, RAD9A and SLC17A9 exhibited moderate diagnostic performance in distinguishing CHB from healthy controls, with AUC values of 0.743, 0.762, and 0.665 respectively. A machine learning model, Adaboost classifier, was constructed to detect CHB by combining exosomal expression of PXN-AS1, RAD9A and SLC17A9. The AUC of the model was 0.983 and 0.924 for CHB detection in train and test dataset respectively. CONCLUSION:Based on multiple RNA-seq data of tissues and plasma exosomes, we identified PXN-AS1, RAD9A, SLC17A9 as diagnostic biomarkers for CHB detection. The model based on three biomarkers showed potential diagnostic value for detecting CHB. Additional validation with a larger sample size is essential to thoroughly assess the reliability of these three biomarkers and the model's performance.

IntroductionSARS-CoV-2 infection is hypothesized to be more severe in immunocompromised patients; however, clinical outcomes in children with inborn errors of immunity (IEI) during the Omicron pandemic in China have not been reported.MethodsThis cohort study retrospectively reviewed 71 SARS-CoV-2-infected children with IEI using nationwide data from the National Center for Children’s Health of China. COVID-19 was diagnosed by a positive rapid antigen or nucleic acid test result.ResultsAmong 71 SARS-CoV-2-infected children with IEI, male preponderance (male: female ratio of ~1.8:1), a median age of 8 years (IQR 3–11), and a predominance of antibody deficiency (19/71, 26.8%) were detected. Most of the patients got infected through household transmission, while a small proportion of them did so during hospital visits. The mean time periods were 3.3 days (n=44) for incubation, 8.4 days for symptoms (n=69), and 8.8 days for viral shedding (n=37). The time to viral shedding was proportional to the symptomatic period (R2 = 0.1243, p=0.0323) and prolonged in children with X- linked agammaglobulinemia. The most common symptoms of COVID-19 were fever, and some children showed only aggravation of the underlying disease. 15% of IEI children progress to pneumonia, 85% require medication, 17% are admitted to hospital, and 4.1% are classified as critical. Previously application of anti- infective medications was associated with an increased risk of hospitalization after COVID-19 infection. Of the 71 children with IEI, all recovered from COVID- 19.ConclusionOverall, Omicron variant did not cause significant life-threatening infections among children with IEI in China, and most of them had a good clinical outcome. Nevertheless, these children exhibit an increased vulnerability to higher hospitalization rates, pneumonia, and severe illness compared to the general pediatric population.

ObjectiveGlucocorticoid (GC) administration has been associated with adverse drug reactions (ADRs) affecting multiple organ systems. While long-term use is widely recognized as a significant independent predictor of ADRs, it is important to note that even short-term use can lead to serious ADRs. The considerable inter-individual variability in ADRs occurrence may be influenced by genetic factors. This study, we present a case of a child who experienced significant weight gain and osteoporosis, following a brief administration of GC.MethodsTo comprehensively investigate the underlying mechanisms, we conducted a genomic analysis utilizing the whole exome sequencing (WES) technique. This analysis encompassed the examination of phase I and phase II metabolism, influx transport, efflux transport, and drug targeting. Additionally, a comprehensive analysis was conducted on a cohort of 52,119 children to determine their ABCB1 rs1045642 genotype, and an additional 37,884 children were tested for their CYP3A5 rs776746 genotype.ResultsThe pharmacogenetic analysis unveiled the presence of a high-risk variant in ABCB1 rs1045642 and a slow metabolism variant in CYP3A5 rs776746, both of which have the potential to substantially contribute to ADRs. The findings of this study indicate that the prevalence of ABCB1 rs1045642 CT type among patients was 47.58%, with TT type accounting for 15.69 % and CC type accounting for 36.73 %. Furthermore, the distribution of CYP3A5 rs776746 CC genotype was observed in 50.54 % of individuals, while CT and TT genotypes were present in 41.15 % and 8.31 % of the population respectively. The distribution of ABCB1 and CYP3A5 genotypes among the pediatric population in China displays notable features. Specifically, for the ABCB1 rs1045642 genotype, less than 50 % of children exhibit intermediate metabotypes. Conversely, among children with the CYP3A5 rs776746 genotype, the predominant cause for enzyme activity is the slow metabolic type, accounting for up to 90 % of cases.ConclusionsConsequently, it is imperative to thoroughly evaluate the impact of allele mutation on the effectiveness and safety of glucocorticoid drugs or other medications metabolized by the ABCB1 and CYP3A5, particularly in the context of Chinese pediatric patients.

Severe congenital neutropenia (SCN) comprises a diverse range of rare hematological disorders characterized by recurrent, often life-threatening infections that manifest within the first months of life. Mutations in the ELANE gene are the most prevalent cause of SCN. While over 230 mutations in ELANE have been documented, including substitutions, frameshifts, nonsense mutations, and splice site alterations, the occurrence of deep intronic mutations has not been previously reported. Herein, we present the case of a young girl who exhibited recurrent fever, respiratory infections, skin abscesses, and gingivitis shortly after birth. Laboratory analysis revealed markedly diminished neutrophil levels alongside elevated monocyte and eosinophil counts. Bone marrow examination disclosed a halt in myelopoiesis maturation. ELANE gene full-length sequencing identified a novel de novo deep intron mutation in ELANE (c.598 + 79G > T), subsequently confirmed by Sanger sequencing. cDNA sequencing of the patient demonstrated aberrant gene splicing. Utilizing a mini-gene splicing assay for ELANE intronic variants, we identified a mutant ELANE allele (c.597 + 1_597 + 83ins) leading to the creation of a premature termination codon (p.Gly200ValfsTer40). Confocal microscopy revealed heightened expression of myeloperoxidase and neutrophil elastase in the patient, suggesting a potential role for the unfolded protein response in the pathogenesis of the deep intron ELANE mutation. In summary, our findings illustrate the first reported instance of de novo deep intron ELANE mutations associated with SCN, underscoring the importance of exploring deep intronic regions in SCN patients lacking identifiable disease-causing gene mutations.

Objective To explore the clinical and genetic features of Aicardi-Goutières syndrome(AGS)caused by IFIH1 gene mutation.Methods We analyzed the clinical features and genetic mutation results of a boy with AGS type 7 and conducted a retrospective review of the literature of the characteristics and clinical features of IFIH1 gene mutations in AGS type 7.Results In the case of this report,the patient,13-year-old boy,exhibited gait abnormalities at age 3.As the condition was progressive,the boy has paraplegia of the lower limbs.The first brain MRI showed no lesions.Rehabilitation therapy in the past several years has shown no improvement.Recent brain CT revealed multiple intracranial calcifications.The whole-exome sequencing identified a heterozygous mutation in the IFIH1 gene(c.2159G＞A,p.R720Q)-a known pathogenic mutation.Through review of the literature,we identified 69 cases of AGS type 7(including the case reported here)which showed that skin and neurological system involvement are most commonly seen.Among these 69 patients,there were 30 different mutations in the IFIH1 gene,all of which are missense mutations.Seven patients had the same gene mutation as the boy in this study does,but their clinical features differed.In terms of treatment,Janus kainase(JAK)inhibitors are commonly used.Addi-tionally,recent reports showed that tocilizumab treatment have been used for this condition.Conclusions AGS7 is a type of I interferonopathy.Growth retardation and nervous system involvement are the most preva-lent.The condition usually involve the skin,blood system,digestive system,kidney,heart,and other or-gans.JAK inhibitors prove effective for this disease.

BACKGROUND:Chronic granulomatous disease (CGD) is a heterogeneous primary immunodeficiency. X-linked (XL) CGD caused by gene defects of CYBB is the most prevalent type of CGD.OBJECTIVE:We aim to understand the clinical and molecule features of XL-CGD secondary to skewed X-chromosome inactivation (XCI) in female.METHODS:We retrospectively reviewed the medical records of a female patient diagnosed with XL-CGD. Flow cytometry was used to detect the respiratory burst function. After restriction enzyme digestion of DNA, XCI was calculated by detecting fluorescent PCR products with capillary electrophoresis. The previously published female XL-CGD cases secondary to skewed XCI was summarized.RESULTS:Clinical data were available for 15 female subjects. The median age of diagnosis was 16 years. Consistent with XL-CGD in males, infection was the most frequent manifestation in the female patients. Catalase-positive pathogens including Serratia marcescens and Staphylococcus aureus infections were the most common pathogens. Autoimmune/autoinflammation manifestations were observed in five patients. Dihydrorhodamine (DHR) assay showed that median %DHR+ values were 6.5% and the values varying with age were observed in 2 patients. All patients had a skewing XCI and there was no consistency between the daughter and carrier mother. Anti-infective treatment was effective in majority and there was no mortality reported in XL-CGD female patients to date.CONCLUSION:XL-CGD should not be neglected in female patients manifested as CGD phenotype and it is necessary to make periodic clinical evaluation of CGD female carriers as the neutrophil oxidative function may decline with aging and increase the risk for infection.

Progressive osseous heteroplasia (POH) is a rare genetic condition that causes progressive ossification. This usually results from an inactivating mutation of the paternal GNAS gene. Herein, we report a case of POH caused by a novel mutation in exon 2 of the GNAS gene. A 5-year-old Chinese boy was referred to our hospital for a growing mass in his right foot. Although laboratory findings were normal, radiographic imaging revealed severe ossification in his right foot and smaller areas of intramuscular ossification in his arms and legs. A de novo mutation (c.175C > T, p.Q59X) in exon 2 of the GNAS gene was identified, prompting a diagnosis of POH. We conducted a systematic literature review to better understand this rare disease. We have discovered that a de novo nonsense mutation in exon 2 of GNAS can lead to POH. Our literature review revealed that ankylosis of the extremities is the primary clinical outcome in patients with POH. Unlike other conditions such as fibrodysplasia ossificans progressiva (FOP), patients with POH do not experience respiratory failure. However, much remains to be learned about the relationship between the type of GNAS gene mutation and the resulting POH symptoms. Further research is needed to understand this complex and rare disease. This case adds to our current understanding of POH and will contribute to future studies and treatments.

Splenic infarction(SI)is a rare clinical phenomenon that occurs when the blood supply to the spleen is interrupted,resulting in tissue ischemia and necrosis[1].There are many causes of SI;in adult patients,cardioembolism,hematologi-cal malignancy,and infectious disease are the most common[2].Rheumatic diseases,especially systemic lupus erythe-matosus(SLE)and granulomatosis with polyangiitis,can also lead to SI[3];however,only a few cases have been reported.There are currently no statistically meaningful data on the etiology of SI in children.Although most patients with SI can recover after conservative treatment,a small number of patients develop complications,such as splenic abscess,splenic rupture,splenic hemorrhage,and hemoperi-toneum,and may even undergo splenectomy in severe cases.

Background Panniculitis, a type of inflammation of subcutaneous fat, is a relatively uncommon condition that usually presents as inflammatory nodules or plaques, with various proposed etiologic factors. The association between panniculitis and enthesitis-related arthritis has not been described previously. Case presentation Herein, we describe a case of a 11-year-old girl who presented with recurrent fever and painful subcutaneous nodules on her extremities and buttocks. Histological examination of the skin biopsy specimen revealed lobular panniculitis. Despite the use of prednisone and mycophenolate mofetil for several months, the patient experienced a relapse of skin lesions and additional symptoms of peripheral joint swelling and inflammatory lumbar pain. She was diagnosed with enthesitis-related arthritis after confirmation by imaging. The panniculitis demonstrated a sustained response when a tumor necrosis factor alpha inhibitor was used for enthesitis-related arthritis. At 2-year follow-up, her skin lesions and arthritis remained stable. Conclusions Although rare, panniculitis can be considered an unusual extra-articular manifestation of enthesitis-related arthritis based on clinical and pathological insights.

Adenosine deaminase (ADA) is a key enzyme in the purine salvage pathway. Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency. To date, few Chinese cases have been reported. We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children’s Hospital and summarized the previously published ADA deficiency cases from China in the literature. Nine patients were identified with two novel mutations (W272X and Q202 =). Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients. The ADA genotype has a major effect on the clinical phenotype. Notably, a novel synonymous mutation (c.606G>A, p.Q202=) was identified in a delayed-onset patient, which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein. Furthermore, the patient showed γδT cells expansion with an increased effect or phenotype, which may be associated with the delayed onset of disease. In addition, we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency. Five patients died with a median age of four months, while two patients received stem cell transplantation and are alive. This study described the first case series of Chinese ADA-deficient patients. Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations in our patients. We identified a synonymous mutation that affected pre-mRNA splicing in the ADA gene, which had never been reported in ADA deficiency. Furthermore, we reported cerebral aneurysm in a delayed-onset patient for the first time. Further study is warranted to investigate the underlying mechanisms.

Cryopyrin-associated periodic syndrome (CAPS) comprises a group of disorders characterized by recurrent bouts of systemic inflammation related to overactivation of inflammasome. So far, neither large cases of the correlation between genotype and phenotype nor treatment strategies have been clearly stated in China. Here, we studied the clinical and genetic characteristics and their correlation from 30 CAPS patients in China. We identified the pathogenesis for novel mutations by activating NLRP3 inflammasome for peripheral cells with ATP plus LPS, compared characteristics with other case series, and analyzed treatment outcomes of these patients. The patients harbored 19 substitutions in NLRP3, and 8 of them were novel mutations. Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials. The correlation of phenotypes and their variants seemed different in our cases, such as T350M, S333G/I/R, and F311V (somatic mosaicism). Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10–20 months follow-up. Patients treated with prednisolone or prednisolone plus thalidomide or methotrexate, tocilizumab, TNF inhibiting agents, and sirolimus achieved only partial remission. Importantly, we firstly identified somatic mosaicism mutation of F311V, which was severe. Our study extended the spectrum of genotype and phenotype and characteristics of their correlations and provided detailed responses to different treatment strategies. These data provide guidance for future diagnosis and management for CAPS.

Purpose Sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss- of-function variant of tRNA nucleotidyl transferase 1 (TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in TRNT1 and an efficacious and novel therapy for SIFD. Methods We retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD. Results Both patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole- exome sequencing of patient 1 identified a previously unreported homozygous mutation of TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p. Met30Val) in TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients. Conclusions Thalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.

Chronic granulomatous disease (CGD) is a heterogeneous primary immunodeficiency characterized by severe bacterial and fungal infections and tissue granuloma formation early in life. Diagnosis of CGD involves the granulocyte function assays and gene mutation analysis. X-linked CGD (XL-CGD) caused by gene defects of CYBB is the most prevalent type of CGD. The clinical data and gene characteristics of a rare female X-chromosome mosaicism leading to inheritance of XL-CGD were reported here. The patient is a 7-year-old boy manifested as recurrent lower respiratory tract infection and failed to thrive. The patient had a history of osteo- myelitis and perianal abscess, with Bacille Calmette-Guérin (BCG) vaccine complications. Respiratory burst of neutrophils was measured with DHR oxidation assay and the histogram showing no significant change in neutrophil fluorescence after stimulation of the patient and the mother's histogram had a pattern of 2 peaks after stimulation. A heterozygous mutation in the CYBB gene (c.866G > A, p.W289X) was identified through inheritance from the patient's mother. Genetic analysis from blood and cheek mucosal cells indicated the female was a mosaicism in CYBB with mutation was present in about 19.5% of her leukocytes. We reported the clinical data and gene characteristics of a rare female X-chromosome mosaicism leading to inheritance of XL-CGD for the first time in China to enrich the understanding of XL-CGD and provide new sights for the hereditary counseling.

The clinical data of a child with ABCB1 rs1045642 T/T genotype and skin photosensitivity induced by Voriconazole were analyzed retrospectively in Beijing Children′s Hospital, Capital Medical University in September 2020.Literature was reviewed to discuss the relationship between ABCB1 genetic polymorphism and Voriconazole pharmacokinetics.The patient was a 6.8-year-old boy, who was diagnosed with primary immunodeficiency disease.Long-term oral Voriconazole was administered for prevention and treatment of fungal infections.Skin photodistributed erythema and pigmentation occurred about 3-4 weeks after treatment.The skin lesions were significantly alleviated about 1 month after the withdrawal of Voriconazole.Gene test showed ABCB1 rs1045642 T/T in the patient.Some studies reported that ABCB1 rs1045642 T/T genotype reduced the clearance rate of Voriconazole.Monitoring such adverse reaction of Voriconazole in clinical practice is important. ABCB1 gene polymorphism is possible to correlate with the pharmacokinetics and adverse reactions of Voriconazole.However, further large-scale clinical studies are warranted to verify it.

背景 西罗莫司(SRL)在患儿中的应用涉及器官移植、自身免疫病、淋巴管畸形、血管畸形、结节性硬化症等疾病,但SRL具有较大的药代动力学变异性,需进行药物监测.目的 提出解决SRL血清药物浓度变化的方案及其原因.设计病例报告.方法 描述2例免疫缺陷病患儿应用SRL治疗6个月的临床资料,分析患儿出现药物浓度异常值的原因,并行文献复习.主要结局指标SRL全血谷浓度(Cmin)达到目标范围5～10 ng·mL-1.结果 例1,SRL与伏立康唑的药物相互作用、CYP3A5 rs776746C/C基因型是导致药物代谢变慢和血药浓度升高的原因,剂量降至初始剂量的20％,SRL血药浓度逐渐恢复至达标范围.例2,CYP3A5基因rs776746C/C型和ABCB1基因rs1045642 T/T型是药物清除率减低和Cmin异常升高的原因,给药剂量降至初始剂量的50％后,SRL血药浓度逐渐下降至正常,治疗浓度一直在达标范围内.结论 在调整治疗方案前考虑确定SRL的Cmin异常值原因的样本、临床和遗传因素应加以考虑,优化患儿的SRL综合治疗管理.