Exome sequencing contributes to identify comorbidities in a rare case of infant ARDS induced by the CD40LG mutation
Xue Gong1, Yunru He1, Guoyan Lu1
1Key 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.
Insights
Early exome sequencing diagnosed X-linked hyper IgM syndrome (XHIGM) in an infant with unexplained respiratory distress. This rare genetic immunodeficiency diagnosis, even with normal immunoglobulin levels, highlights the importance of genetic testing in infants with severe infections.
Area of Science:
- Pediatric Pulmonology
- Clinical Genetics
- Immunology
Background:
- Acute respiratory distress syndrome (ARDS) presents a significant mortality risk in infants with specific diseases.
- Early diagnosis and intervention are crucial for reducing infant mortality associated with ARDS.
- This report details a rare case utilizing exome sequencing for the early diagnosis of immunodeficiency in an infant.
Observation:
- A four-month-old infant presented with severe respiratory distress, hypoxemia, and unexplained lung lesions.
- Initial viral testing was largely negative, with only rhinovirus detected.
- Family history revealed a deceased sibling due to severe infection, prompting genetic investigation.
Findings:
- Exome sequencing identified a CD40LG mutation, diagnosing X-linked hyper IgM syndrome (XHIGM).
- The infant had normal plasma immunoglobulin levels, atypical for XHIGM, underscoring the diagnostic challenge.
- Treatment with intravenous immunoglobulin (IVIG) led to clinical improvement and enhanced lung CT scans.
Implications:
- Exome sequencing is vital for diagnosing immunodeficiencies in infants with unexplained infections, especially with a positive family history.
- Genetic testing can identify XHIGM even when plasma immunoglobulin levels are normal, masking typical presentation.
- This case represents the youngest infant diagnosed with molecularly confirmed XHIGM, advancing early detection strategies.
Background:
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.
Case Presentation:
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.
Conclusion:
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.
