A retrospective study of infantile-onset Takayasu arteritis: experience from a tertiary referral center in China.

Objective: Takayasu artery (TAK) is a chronic inflammatory disease that mainly affects the aorta and its major branches and is rarely reported in infants. We aimed to summarize the clinical features of infant TA (I-TA) in a tertiary care center. Methods: We performed a retrospective study involving 10 infants diagnosed with TAK. A comprehensive evaluation of clinical, laboratory, radiographic features, disease activity, treatment and outcomes was carried out. Results: A consecutive cohort was composed of 8 girls and 2 boys, with an age at diagnosis of 11.1 (1.7-36) months. The median time to diagnosis and the average time to follow-up were 9.5 days (2-235 days) and 10.9 (1-21) months, respectively. The most common initial manifestations were malaise (80%), fever (70%), hypertension (50%) and rash (30%). The mean Pediatric Vasculitis Activity Score (PVAS), Takayasu Clinical Activity Score (ITAS-2010) and ITAS-A scores were 2.8/63, 2.6/51, and 5.6/54, respectively. All patients had aberrant laboratory parameters. The most common lesions were in the thoracic aorta (60%) and abdominal aorta (60%). Corticosteroids combined with cyclophosphamide followed by long-term mycophenolate mofetil were initiated in most cases (70%). Biologics were attempted in 5 cases. Mortality was 40%. Conclusions: It is challenging to diagnose TAK in infants in a timely manner. Considering the more vessels involved, more severe inflammation and higher mortality, aggressive treatment is warranted in infants. GCs and CYC treatment seem to be effective.

Single-cell transcriptomes of kidneys in a 6-month-old boy with Denys-Drash syndrome reveal stromal cell heterogeneity in the tumor microenvironment.

Background: Denys-Drash syndrome (DDS) is a rare disease characterized with pseudohermaphroditism, nephroblastoma (also known as Wilms tumor), and diffuse mesangial sclerosis. The therapy for DDS is largely supportive, i.e. surgery and chemotherapy for Wilms tumor and renal replacement therapy. Due to the limited understanding of the pathogenesis, precision therapy for DDS is yet to be explored. We sought to explore the cellular components and interactions in kidney tissues from an infant with DDS. Methods: Whole-exome sequencing was performed to examine the mutations associated with DDS. Single-cell RNA sequencing (scRNA-seq) was performed to explore the heterogenicity of kidney tissue samples. Results: A 6-month-old infant with bilateral Wilms tumors and genital ambiguity was diagnosed as having DDS. Whole exome sequencing revealed a novel de novo mutation (p.F185fs*118) in exon 1 of WT1. scRNA-seq was performed in tissue samples from bilateral Wilms tumors and the normal kidney from this infant. Fibroblasts, myocytes, epithelial cells, endothelial cells, and mononuclear phagocytes (MPs) ranked at the top of the 31 135 total cells. Fibroblasts and myocytes were dominant in the Wilms tumor samples. In contrast, most epithelial cells and endothelial cells were found in normal kidney tissues. CD44 and TUBA1A were significantly changed in myocyte subclusters, which may contribute to chemotherapy drug resistance. Macrophages intensively interacted with cancerous cells, including fibroblasts, epithelial cells, and myocytes. Conclusions: A novel mutation (p.F185fs*118) in exon 1 of WT1 was identified in an infant with DDS. scRNA-Seq revealed the heterogenicity of cellular components in Wilms tumors and kidney tissues, shedding light on the pathogenesis of DDS.

Diagnostic yield and novel candidate genes for neurodevelopmental disorders by exome sequencing in an unselected cohort with microcephaly.

OBJECTIVES: Microcephaly is caused by reduced brain volume and most usually associated with a variety of neurodevelopmental disorders (NDDs). To provide an overview of the diagnostic yield of whole exome sequencing (WES) and promote novel candidates in genetically unsolved families, we studied the clinical and genetic landscape of an unselected Chinese cohort of patients with microcephaly. METHODS: We performed WES in an unselected cohort of 103 NDDs patients with microcephaly as one of the features. Full evaluation of potential novel candidate genes was applied in genetically undiagnosed families. Functional validations of selected variants were conducted in cultured cells. To augment the discovery of novel candidates, we queried our genomic sequencing data repository for additional likely disease-causing variants in the identified candidate genes. RESULTS: In 65 families (63.1%), causative sequence variants (SVs) and clinically relevant copy number variants (CNVs) with a pathogenic or likely pathogenic (P/LP) level were identified. By incorporating coverage analysis to WES, a pathogenic or likely pathogenic CNV was detected in 15 families (16/103, 15.5%). In another eight families (8/103, 7.8%), we identified variants in newly reported gene (CCND2) and potential novel neurodevelopmental disorders /microcephaly candidate genes, which involved in cell cycle and division (PWP2, CCND2), CDC42/RAC signaling related actin cytoskeletal organization (DOCK9, RHOF), neurogenesis (ELAVL3, PPP1R9B, KCNH3) and transcription regulation (IRF2BP1). By looking into our data repository of 5066 families with NDDs, we identified additional two cases with variants in DOCK9 and PPP1R9B, respectively. CONCLUSION: Our results expand the morbid genome of monogenic neurodevelopmental disorders and support the adoption of WES as a first-tier test for individuals with microcephaly.

[Diagnostic value of 64 multislice CT in typing of congenital aortic anomaly in neonates and infants].

OBJECTIVE: To study diagnostic value of 64 multislice CT in typing of congenital aortic anomaly in neonates and infants. METHODS: 120 pediatric patients (under one year of age) with congenital heart disease (CHD) underwent 64 contrast-enhanced MSCT before a corrective operations. The diagnostic sensitivity, specificity and accuracy of 64 MSCT were evaluated and also compared with those of echocardiography with Doppler. The patients were randomly assigned to two groups (72 and 48 persons) respectively according to tube tension of 80 and 100 kV. The differences of the image qualities were compared between them. RESULTS: 36 congenital aortic anomalies were found (36/120, 30%) by 64 MSCT, which were furtherly distinguished into 2 cases in double aortic arch, 2 cases in left-sided aortic arch with aberrant right subclavian artery, 22 cases in right aortic arch (6 cases in right-sided aortic arch with aberrant left subclavian artery, 12 cases in right aortic arch with mirror image branching), 10 cases in coarctation of aorta. Diagnostic sensitivity, specificity and accuracy of 64 MSCT were all 100%. By contrast, those of echocardiography with Doppler were 27.8%, 97.6%, 76.7%, respectively. The quality scores were 4.69 ± 0.52, 4.58 ± 0.58 at 80 kV and 100 kV, respectively. No significant statistical difference was found between them (t = 1.08, P = 0.28). CONCLUSION: MSCT allows a detailed assessment of the anatomy of congenital aortic anomaly, which can be used as an important supplementary method in diagnosing CHD and offer important information for operation. 80 kV should be selected in CHD patients less than one year old for CT examination to reduce radiation exposure.