A Novel Hypomorphic ZAP70 Mutation with Normal CD8+ T Cells Count

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A Novel Hypomorphic ZAP70 Mutation with Normal CD8+ T Cells Count

Introduction

In the realm of immunodeficiency disorders, understanding rare genetic mutations is crucial for accurate diagnosis and appropriate treatment. ZAP70 deficiency is one such condition. It is a rare autosomal recessive primary immunodeficiency. Typically, it is characterized by absent CD8+ T cells and non-functional CD4+ T cells. This can lead to a host of problems, including recurrent bacterial, viral, and opportunistic infections, diarrhea, and autoimmune diseases. However, ZAP70 hypomorphic mutations show clinical heterogeneity, which makes diagnosis challenging.

Case Presentation

We present a case of a 16-month-old girl. After birth, she received a Bacillus Calmette-Guerin vaccination. Two months later, the vaccination site became purulent. At 5 months old, she was diagnosed with severe fungal and bacterial pneumonia. A left armpit lump with pus showed acid-fast bacillus positive, and plasma and sputum showed cytomegalovirus (CMV)-deoxyribonucleic acid positive. Ultrasound revealed multiple enlarged left axillary and inguinal lymph nodes, as well as hepatosplenomegaly. There were also extensive lesions in her fundus oculi due to CMV infection. At 11 months, she had continuous liver dysfunction. Ultrasound showed small nodules in the liver and multiple small lymph nodes in the hepatic hilar and pancreatic head. Currently, she has oral candidiasis (thrush).

Immunologic Investigations

The immunologic investigations are detailed in Table 1. Notably, the patient did not show an observable decrease in CD8+ T cells. Autoantibodies were tested and all results were negative. Roifman et al previously described that the CD8+ T cell count increased with time, suggesting the thymus might participate in residual functions of CD8+ T cell maturation. This case shows that the absence of normal CD8+ T cells cannot be the exclusion criterion for diagnosing ZAP70 mutation, making early identification more difficult.

Genetic Analysis

The patient is from a non-consanguineous family with a healthy older sister. Next-generation sequencing identified two heterozygous ZAP70 mutations (c.703-1G>A and c.1523C>A [p. P508H]). The c.703-1G>A mutation was inherited from her father, leading to a splice variant lacking exon 6. The c.1523C>A mutation was from her mother and had not been reported before. Using tools like SIFT (Sorting Intolerant From Tolerant), PolyPhen2, and MutationTaster, the predicted functional effects of c.1523C>A were determined. PolyPhen-2 predicted it was probably damaging to the protein with a score of 1.000. MutationTaster predicted it was disease-causing with a probability of 0.9999. SIFT predicted it was damaging on protein function with a score of 0.00 (<0.05).

Treatment Considerations

Currently, the patient’s family is searching for a suitable unrelated hematopoietic stem cell donor. Hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for ZAP70 deficiency, providing excellent long-term immune function. However, more cases need to be included in clinical investigations to prove the effects of HSCT on the heterogeneity of ZAP70 mutations.

Conclusion

This case highlights a novel hypomorphic ZAP70 mutation with normal CD8+ T cells count. It emphasizes the importance of considering genetic mutations even when typical immunologic markers (like absent CD8+ T cells) are not present. Further research is needed to better understand the implications of such mutations and the optimal treatment strategies.

References

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doi: 10.1097/CM9.0000000000000911

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