A Distinct Feature of T Cell Subpopulations in a Patient with CHARGE Syndrome and Omenn Syndrome
A Distinct Feature of T Cell Subpopulations in a Patient with CHARGE Syndrome and Omenn Syndrome
复制标题
CHARGE 综合征和 Omenn 综合征患者 T 细胞亚群的显着特征
DOI：
10.1007/s10875-020-00875-7
复制
发表时间：
2020
影响因子：
9.1
通讯作者：
Onodera Masafumi
中科院分区：
文献类型：
--
作者：
Uchiyama Toru;Kawakami Saori;Masuda Hiroshi;Yoshida Kazue;Niizeki Hironori;Mochizuki Emi;Edasawa Kaori;Ishiguro Akira;Onodera Masafumi
编辑认为，Charge综合征(眼缺损、心脏缺陷、克隆性闭锁、生长发育迟缓、生殖道发育不良和耳朵异常)是一种遗传性疾病，由编码色域解旋酶DNA结合蛋白7(CHD7)的基因常染色体显性突变引起，该突变影响几个信号通路并控制器官发育[1]。Charge综合征患者的临床表现与染色体22q11有重叠。2缺失综合征，也称为DiGeorge综合征(DGS)，其中TBX1基因的缺失会导致胸腺发育不全、圆锥干心脏缺陷和甲状旁腺功能减退症。尽管CHD7和TBX1的相互作用尚未明确，但共同的胚胎途径的存在可以解释胸腺发育异常[2]和胸腺再生障碍症患者存在T细胞缺陷的潜在发病机制，这是严重联合免疫缺陷(SCID)的特征。缺乏胸腺处理也允许自身反应性T细胞的寡克隆性增殖，从而导致常染色体隐性遗传性SCID中常见的Omenn综合征[1]；然而，临床病程和免疫表型的长期变化很少有报道。在这里，我们报告了Omenn综合征患者症状的波动和T细胞表型的显著变化。出生时有多种异常的男性患者，包括心脏畸形、生殖器发育不全、面神经麻痹和外耳畸形，在临床试验中淋巴细胞数量减少和低钙血症(表S1)。采用流式细胞仪(FCM)分析的免疫表型显示CD3+T细胞的数量明显减少(图4)。S1)。过渡性B细胞(CD19+IgMhiCD38hi)频率升高提示B细胞成熟受阻。实时定量聚合酶链式反应分析T细胞受体切除环水平为0拷贝/μg DNA。这些数据表明这是一种T细胞缺陷表型。磁共振成像显示胸腺完全消失。而患者核型正常，未发现22q11号染色体微缺失。2经荧光原位杂交(FISH)分析，患者出现眼部缺损，提示患有Charge综合征。基因组DNA测序分析发现CHD7存在c.2238+2T>；C杂合性错义突变。预防性应用抗生素和抗真菌药物可预防严重感染。在3个月大的时候，他出现了红斑性丘疹、腹泻和脱发，并伴有CD4+和CD8+T细胞以及嗜酸性粒细胞数量的增加(图1a，图1)。S2)。CD4+T细胞和CD8+T细胞均表现为记忆表型(CD45RO+)，并在人类白细胞抗原DR的表达下高度活化。S3、S4)。对T细胞受体(TCRV)β谱系的分析显示，CD8+T细胞中存在明显的扭曲模式(图1B)。T细胞的再生仍然受损，最近的胸腺移居(RTE)T细胞(CD3+CD4+CD45RA+CD31+)缺失(数据未显示)。X/Y FISH排除了母体T细胞植入的可能性；观察到这些特征类似于Omenn综合征
To the editor, CHARGE syndrome (ocular coloboma, heart defects, clonal atresia, retarded growth and development, genitourinary hypoplasia, and ear abnormalities) is a genetic disorder caused by an autosomal dominant mutation in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7) that affects several signaling pathways and controls organ development [1]. Patients with CHARGE syndrome have clinical overlap with chromosome 22q11. 2 deletion syndrome, also referred to as DiGeorge syndrome (DGS), in which the insufficiency of the TBX1 gene causes thymic hypoplasia, conotruncal cardiac defects, and hypoparathyroidism. Although the interaction of CHD7 and TBX1 has not been clearly identified, the presence of a shared embryonic pathway can explain the underlying pathogenesis of abnormal thymic development [2] and the presence of T cell deficiency in patients with thymic aplasia, a feature of severe combined immunodeficiency (SCID). The lack of thymic processing also allows the oligoclonal proliferation of autoreactive T cells, which causes Omenn syndrome [1], typically observed in autosomal recessive SCID; however, the long-term changes in clinical course and immunophenotyping have rarely been reported. Here, we report the fluctuations in symptoms of Omenn syndrome with remarkable changes in T cell phenotype in a patient with CHARGE syndrome. The male patient who had several anomalies at birth, including heart malformations, genital hypoplasia, facial nerve palsy, and external ear malformation, presented a decreased number of lymphocytes and hypocalcemia in clinical tests (Table S1). Immunophenotyping using flow cytometric (FCM) analysis showed a marked decrease in the number of CD3+ T cells (Fig. S1). An increase in the frequency of transitional B cells (CD19+ IgMhiCD38hi) implied impaired maturation of B cells. The level of T cell receptor excision circles (TRECs) in a quantitative real-time polymerase chain reaction (PCR) analysis was 0 copies/μg DNA. These data suggested a T cell-deficient phenotype. Magnetic resonance imaging showed the complete absence of thymus. Whereas the patient showed a normal karyotype and no microdeletion of chromosome 22q11. 2 by fluorescent in situ hybridization (FISH) analysis, he presented with coloboma of the eye, which implied that he had CHARGE syndrome. The sequencing analysis of genomic DNA revealed a c. 2238+ 2T> C heterozygous missense mutation in CHD7.The prophylactic administration of antibiotics and antifungal drugs prevented severe infections in the patient. At 3 months of age, he developed an erythematous papular rash, diarrhea, and alopecia, with an increase in numbers of CD4+ and CD8+ T cells, as well as eosinophils (Fig. 1a, Fig. S2). Both CD4+ and CD8+ T cells displayed memory phenotype (CD45RO+) and were highly activated with the expression of HLA-DR (Figs. S3, S4). Analysis of T cell receptor (TCR) Vβ repertoire showed a significantly skewed pattern in CD8+ T cells (Fig. 1b). The regeneration of T cells was still impaired, as indicated by the absence of recent thymic emigrant (RTE) T cells (CD3+ CD4+ CD45RA+ CD31+)(data not shown). Engraftment of maternal T cells was ruled out by X/Y FISH; these features resembled Omenn syndrome, observed