A Novel Hypomorphic Z-Chain-Associated Protein Tyrosine Kinase 70 kDa Mutation with Normal CD8+ T Cells Count
Zeta-chain-associated protein tyrosine kinase 70 kDa (ZAP70) deficiency is a rare autosomal recessive primary immunodeficiency disorder characterized by the absence of CD8+ T cells and non-functional CD4+ T cells. This condition typically leads to recurrent bacterial, viral, and opportunistic infections, diarrhea, and autoimmune diseases. Despite the rarity of ZAP70 deficiency, approximately 18 pathogenic mutations have been identified in fewer than 30 patients. Hypomorphic mutations of ZAP70, which result in partial loss of function, exhibit significant clinical heterogeneity, including Epstein-Barr virus-associated lymphoproliferative disorders, late-onset immunodeficiency, and silent brain infarcts. The use of next-generation sequencing technology has become a predominant diagnostic approach for identifying these mutations.
This case report presents a 16-month-old girl with heterozygous ZAP70 mutations, a unique presentation of the disorder characterized by a normal CD8+ T cell count. The patient’s clinical course began with a Bacillus Calmette-Guerin (BCG) vaccination at birth, which led to purulent inflammation at the vaccination site two months later. By the age of five months, she developed severe fungal and bacterial pneumonia, accompanied by a left armpit lump that tested positive for acid-fast bacilli. Plasma and sputum samples were positive for cytomegalovirus (CMV) DNA. Ultrasound imaging revealed multiple enlarged lymph nodes in the left axillary and inguinal regions, as well as hepatosplenomegaly. Fundus examination showed extensive lesions due to CMV infection. At 11 months of age, the patient experienced persistent liver dysfunction, with ultrasound findings indicating small liver nodules and multiple small lymph nodes in the hepatic hilar and pancreatic head regions. Additionally, she developed oral candidiasis (thrush), a common manifestation of immunodeficiency.
Immunologic investigations were conducted at various ages, and the results are summarized in Table 1. Notably, the patient did not exhibit a significant reduction in CD8+ T cells, which is atypical for ZAP70 deficiency. Autoantibody testing yielded negative results. Previous studies, such as those by Roifman et al., have suggested that CD8+ T cell counts may increase over time, possibly due to residual thymic function in CD8+ T cell maturation. This case highlights that the absence of normal CD8+ T cells should not be considered an exclusion criterion for diagnosing ZAP70 mutations, complicating early identification of the disorder.
The patient’s family history revealed no consanguinity, and she has a healthy older sister. Next-generation sequencing was employed to identify the disease-causing gene, revealing two heterozygous ZAP70 mutations: c.703-1G>A and c.1523C>A (p. P508H). The c.703-1G>A mutation, inherited from the father, results in a splice variant lacking exon 6. The c.1523C>A mutation, inherited from the mother, has not been previously reported. Functional predictions for the c.1523C>A variant were performed using SIFT, PolyPhen2, and MutationTaster. PolyPhen2 predicted the variant to be probably damaging with a score of 1.000, MutationTaster predicted it to be disease-causing with a probability of 0.9999, and SIFT predicted it to be damaging to protein function with a score of 0.00.
The patient’s family is currently seeking a suitable unrelated hematopoietic stem cell donor. Hematopoietic stem cell transplantation (HSCT) is the definitive life-saving therapy for ZAP70 deficiency, offering excellent long-term immune function. However, further clinical investigations are necessary to evaluate the efficacy of HSCT in patients with hypomorphic ZAP70 mutations, given the observed clinical heterogeneity.
Laboratory parameters for the patient at different ages are detailed in Table 1. Key findings include elevated natural killer (NK) cell percentages at 5 and 14 months, increased CD3+CD4+ percentages at 5 and 8 months, and a normal CD3+CD8+ percentage throughout the observation period. The CD4/CD8 ratio was elevated at 5 and 8 months but normalized by 12 months. Immunoglobulin levels showed elevated IgG at 5 months, low IgA at 8 months, and low IgM at 12 months. White blood cell counts were elevated at 8 months, with increased lymphocytes and monocytes at multiple time points. Hemoglobin levels were low at 5 and 12 months, while platelet counts remained within the normal range.
This case underscores the importance of considering ZAP70 deficiency even in the absence of typical CD8+ T cell depletion. The use of advanced genetic sequencing technologies is critical for accurate diagnosis, particularly in cases with atypical presentations. The identification of a novel ZAP70 mutation (c.1523C>A) expands the spectrum of known pathogenic variants associated with this disorder. Further research is needed to understand the functional consequences of hypomorphic ZAP70 mutations and to optimize therapeutic strategies, including HSCT, for affected individuals.
doi.org/10.1097/CM9.0000000000000911
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