Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China.
BMC Med Genomics. 2022 Jul 8;15(1):153. doi: 10.1186/s12920-022-01303-y.
Acute respiratory distress syndrome (ARDS) causes significant mortality in young children with certain diseases. Early diagnosis and treatment can reduce infant mortality. Here, we report a rare case of exome sequencing in the early diagnosis of immunodeficiency in an infant.
A four-month-old full-term male infant presented with severe shortness of breath, hypoxemia, and unexplained parenchymal lung lesions. A series of examinations were performed to search for potential culprit viruses but negative results were obtained with the only exception being the rhinovirus that tested positive. The child's family history revealed he had a brother who died of severe infection at the age of two years. We performed an exome sequencing analysis and a mutation analysis of CD40LG to obtain genetic data on the patient. Besides, we used flow cytometry to measure the CD40LG expression levels of activated T cells. A retrospective review of all the CD40LG mutant-induced X-linked hyper IgM syndromes (XHIGM) had been conducted to assess the differences between clinical and genetic molecular features. Finally, a regular intravenous immunoglobulin (IVIG) regimen led to steady breathing, the correction of hypoxemia, and a progressive improvement of lung CT scans. During follow-up, the patient received an IVIG regimen and his CT images improved. Moreover, his parents took advantage of pre-implantation genetic testing with in vitro fertilization to have a healthy twin offspring who did not carry such a mutation according to the early exome sequencing for the proband. Compared with other CD40LG mutant cases in our center, this proband displayed a normal plasma immunoglobulin level and he should be the youngest infant to have a molecular diagnosis of XHIGM.
Usually, XHIGM would not be suspected with a normal plasma immunoglobulin concentration. However, as we could not identify a potential comorbidity or risk factor, exome sequencing helps target this patient's real facts. Thus, this case report calls for exome sequencing to be performed in the case of unexplained infections when immunodeficiency is suspected after general immunological tests, especially for cases with a contributive family history among infants as the maternal transfused immunoglobulin might mask immune deficiency.
急性呼吸窘迫综合征（ARDS）可导致某些疾病的幼儿死亡率显著升高。早期诊断和治疗可降低婴儿死亡率。在此，我们报告了一例通过外显子组测序对婴儿免疫缺陷进行早期诊断的罕见病例。
一名 4 个月大的足月男婴因严重呼吸急促、低氧血症和不明原因的实质肺病变就诊。进行了一系列检查以寻找潜在的罪魁祸首病毒，但除了检测出阳性的鼻病毒外，其余结果均为阴性。患儿家族史显示，其有一个哥哥，2 岁时死于严重感染。我们进行了外显子组测序分析和 CD40LG 突变分析，以获取患者的遗传数据。此外，我们还使用流式细胞术测量了活化 T 细胞的 CD40LG 表达水平。回顾性分析了所有 CD40LG 突变引起的 X 连锁高免疫球蛋白血症（XHIGM）的病例，以评估临床和遗传分子特征之间的差异。最后，采用常规静脉注射免疫球蛋白（IVIG）方案，患儿呼吸逐渐平稳，低氧血症得到纠正，肺部 CT 扫描逐渐改善。随访中，患儿接受 IVIG 方案治疗，CT 图像改善。此外，患儿父母利用体外受精的胚胎植入前基因检测，生下了一对未携带该突变的健康双胞胎。与我们中心的其他 CD40LG 突变病例相比，该患儿的血浆免疫球蛋白水平正常，是目前已知的最早接受 XHIGM 分子诊断的婴儿。
通常情况下，当免疫球蛋白浓度正常时，不会怀疑 XHIGM。然而，由于我们无法确定潜在的合并症或危险因素，外显子组测序有助于明确该患者的真实情况。因此，当怀疑免疫缺陷且常规免疫检查无法明确病因时，建议对不明原因感染的患者进行外显子组测序，尤其是对于有家族史的婴儿，因为母体输注的免疫球蛋白可能会掩盖免疫缺陷。
