Zeta(ζ)-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare autosomal recessive primary immunodeficiency disease. Little is known about this disease. In this study, we report two patients to extend the range of clinical phenotypes and immunophenotypes associated with ZAP-70 mutations. We describe the clinical, genetic, and immunological phenotypes of two patients with ZAP-70 deficiency in China, and the data are also compared with the literature. Case 1 presented with leaky severe combined immunodeficiency with low to the absence of CD8 + T cells, while case 2 suffered from a recurrent respiratory infection and had a past medical history of non-EBV-associated Hodgkin’s lymphoma. Sequencing revealed novel compound heterozygous mutations in ZAP-70 of these patients. Case 2 is the second ZAP-70 patient presenting a normal CD8 + T cell number. These two cases have been treated with hematopoietic stem cell transplantation. Selective CD8 + T cell loss is an essential feature of the immunophenotype of ZAP-70 deficiency patients, but there are exceptions. Hematopoietic stem cell transplantation can provide excellent long-term immune function and resolution of clinical problems.

为了探讨湿疹-血小板减少伴免疫缺陷综合征(WAS)的特殊表型.回顾性分析2017年3月重庆医科大学附属儿童医院风湿免疫科收治的1例以单核细胞增多为特征的WAS病例的临床资料及实验室检查结果,并复习相关文献.结果发现,患儿出生后以血小板减少及贫血为主要表现,伴肝脾肿大及间断血便,血常规提示白细胞、中性粒细胞及单核细胞增高,血红蛋白及血小板降低,外周血及骨髓原始幼稚细胞不高,考虑幼年型粒单核细胞白血病(JMML)可能.JMML相关基因和染色体核型未见异常.由于WAS蛋白(WASP)明显表达减少,WAS基因存在一处半合子突变(c.151G＞T,p.V51F),最终确诊为WAS.WAS临床表型变异大.对于早发血小板减少的男婴,建议检测WAS蛋白和WAS基因进行筛查.

Wiskott-Aldrich syndrome (WAS) is a disorder characterized by rare X-linked genetic immune deficiency with mutations in the Was gene, which is specifically expressed in hematopoietic cells. The spleen plays a major role in hematopoiesis and red blood cell clearance. However, to date, comprehensive analyses of the spleen in wild-type (WT) and WASp-deficient (WAS-KO) mice, especially at the transcriptome level, have not been reported. In this study, single-cell RNA sequencing (scRNA-seq) was adopted to identify various types of immune cells and investigate the mechanisms underlying immune deficiency. We identified 30 clusters and 10 major cell subtypes among 11,269 cells; these cell types included B cells, T cells, dendritic cells (DCs), natural killer (NK) cells, monocytes, macrophages, granulocytes, stem cells and erythrocytes. Moreover, we evaluated gene expression differences among cell subtypes, identified differentially expressed genes (DEGs), and performed enrichment analyses to identify the reasons for the dysfunction in these different cell populations in WAS. Furthermore, some key genes were identified based on a comparison of the DEGs in each cell type involved in specific and nonspecific immune responses, and further analysis showed that these key genes were previously undiscovered pathology-related genes in WAS-KO mice. In summary, we present a landscape of immune cells in the spleen of WAS-KO mice based on detailed data obtained at single-cell resolution. These unprecedented data revealed the transcriptional characteristics of specific and nonspecific immune cells, and the key genes were identified, laying a foundation for future studies of WAS, especially studies into novel and underexplored mechanisms that may improve gene therapies for WAS.

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by mutations in LIG4. Patients suffer from a broad spectrum of clinical problems, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and a predisposition to autoimmune diseases and malignancy. In this study, the clinical, molecular, and immunological characteristics of 15 Chinese patients with LIG4 deficiency are summarized in detail. p.R278L (c.833G>T) is a unique mutation site present in the majority of Chinese cases. We conducted pedigree and haplotype analyses to examine the founder effect of this mutation site in China. This suggests that implementation of protocols for genetic diagnosis and for genetic counseling of affected pedigrees is essential. Also, the search might help determine the migration pathways of populations with Asian ancestry.

目的 分析Frasier综合征的临床病理及致病基因特征.方法 回顾分析1例Frasier综合征患儿的临床、病理特点,基因检测结果及诊治过程,并复习相关文献.结果 患儿具有女性外生殖器,染色体核型46,XY,性腺发育不良(双侧卵巢未发育);肾病起病年龄为6岁,激素治疗无效.先后使用他克莫司、利妥昔单抗,虽血清白蛋白、胆固醇有所改善,肾功能无异常,但尿蛋白始终不能转阴.肾脏活检病理示局灶节段性肾小球硬化症,非特殊型,伴部分肾小球硬化.未发现性腺肿瘤、Wilms瘤等.基因检测WT1基因外显子9的c.1432+5G>A剪接突变,为自发突变,已报道与Frasier综合征致病相关.结论 Frasier综合征临床表现主要为进展性肾病、男性假两性畸形、泌尿生殖系统畸形,与WT1基因突变有关.

目的 探讨儿童原发性肾病综合征( primary nephritic syndrom,PNS)并发颅内静脉血栓(cerebral venous sinus thrombosis,CVST)患儿的临床及实验室检查特征.方法 系统性回顾分析2013年1月至2018年5月深圳市儿童医院住院的5例PNS并发CVST患儿的临床资料,对患儿临床表现,影像学、实验室检查结果,治疗及随访结果进行分析.结果 5例患儿均有明显浮肿、头晕、头痛等精神症状,2例有呕吐,查体无神经系统阳性体征.所有患儿实验室检查血清白蛋白<20 g/L,血浆纤维蛋白原(Fib) >4 g/L,D￣二聚体>1 000 mg/L,抗凝血酶Ⅲ<100 mg/L.经抗凝治疗后,Fib和D￣二聚体降低至正常范围. 5例患儿给予尿激酶溶栓,低分子肝素钙皮下注射,双嘧达莫口服抗凝治疗,3例还加用华法林口服抗凝治疗,监测血浆凝血酶原时间测定国际标准化比值( prothrombin time￣international normal￣ized ratio,PT￣INR),维持在2. 0～2. 5之间.平均住院时间(20 ± 5)d. 5例患儿治疗后症状均明显改善.患儿出院后6～36个月随访头颅MRI增强+MRV显示颅内异常信号均有不同程度吸收,临床痊愈.结论 PNS并发CVST易发生于乙状静脉窦、上矢状窦. D￣二聚体>1 000 ng/ml应高度警惕.PNS患儿出现头晕、头痛、呕吐等神经精神症状时,应及时完善头颅MRI等相关检查,有助于诊断PNS并发CVST.早期诊断及抗凝治疗PNS并发CVST,预后良好.

OBJECTIVE:To explore the clinical characteristics of a patient with Sensenbrenner syndrome (also called cranioectodermal dysplasia type 3) caused by mutation of intraflagellar transport (IFT) 43 gene.METHODS:The clinical data of the patient was retrospectively analyzed. The target genes was the patient were captured and subjected to next generation sequencing. Suspected mutations were verified through Sanger sequencing.RESULTS:The patient, a-13 year-and-5-month-old girl, was admitted for anemia and renal dysfunction for 8 months. Clinically, she has featured short stature, short limbs, brachydactylia, tooth agenesis, and retinal dystrophy, high-degree myopia, and chronic renal failure. Gene sequencing showed that she has carried a homozygous c.1A>G (p.M1V) mutation of the IFT43 gene, for which both of her parents were heterozygous carriers.CONCLUSION:c.1A>G (p.M1V) mutation of the C14ORF179/IFT43 gene is the cause for praecox chronic renal failure in children. Genetic testing can facilitate the diagnosis of this rare disorder. For affected families, prenatal diagnosis should be provided.

OBJECTIVE:To explore the clinical phenotype, genetic variant, treatment and prognosis of a child with mosaic variegated aneuploidy syndrome (MVAS).METHODS:Immunological marker screening, chromosomal karyotyping and whole exome sequencing were carried out.RESULTS:The 1-year-11-month old girl has featured severe growth retardation, feeding difficulty, short stature, microcephaly, facial anomalies, scoliosis, visual impairment, hypotonia, chylothorax, and renal lesions. Karyotype analysis of peripheral blood lymphocytes has discovered variegated aneuploidy cells (6/11). DNA sequencing has identified compound heterozygous c.826delG (p.Asp276Metfs*21) and c.2441G>A (p.Arg814His) variants in the BUB1B gene, which were inherited from her father and mother, respectively.CONCLUSION:The compound heterozygous variants of the BUB1B gene probably underlie the pathogenesis in this patient.

Objective To explore the clinical features and genetic characteristics of primary immunodeficiency disease (PIDs) with skin symptoms in children. Methods The clinical data of PIDs with skin symptoms in 15 children from January 2014 to March 2017 were analyzed retrospectively. Results The median age at onset in 15 children was 4 months (neonatal period to 11 years 8 months). All of them showed obvious skin symptoms, including eczema or chilblain rash, pustular psoriasis, skin infections, subcutaneous hemorrhage or skin ecchymosis, ichthyosiform erythroderma, progeroid appearance, or other cutaneous vasculitis. The accompanying manifeslations included recurrent infections, auto inflammation, autoimmunity, growth retardation, or lymphoid proliferation, and impairment of brain, lung, kidney and other important organs. Eosinophil counts were increased in 5 children, IgE levels were elevated in 5 children, and 4 children were abnormal in both indicators. Gene detection showed WAS, RNASEH2C, NLRP12, IL36RN, NRAS, PIK3CD, STAT1, FOXP3, STAT3, DOCK8, TYK2, SPINK5, NBAS or ITGB2 gene mutations, respectively. Two children died from multiple organ dysfunction syndrome, 1 child was lost for follow up, the remaining 12 children survived and were under the individualized treatment. Conclusions A variety of PIDs can have skin symptoms. When accompanied by recurrent infections, auto inflammation, autoimmune, growth retardation, or lymph proliferation, PIDs should be considered, and gene detection is helpful for the diagnosis.