Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review

Abstract

Background: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.

Keywords: CD8+ T cell lymphopenia; Primary Immunodeficiency; ZAP-70 deficiency; ZAP70 mutation; combined immunodeficiency.

Figure 1

Schematic structure of the ZAP70 gene and location of reported mutations in patients with ZAP-70 deficiency. The indicated ZAP-70 domains are the amino-terminal SH2 domain (N-SH2), interdomain A (I-A), carboxy-terminal SH2 domain (C-SH2), interdomain B (I-B), and the kinase domain. The disease-causative mutations in ZAP-70 deficiency occur throughout the full-length gene without obvious hotspots although the majority of mutations resided within the Kinase domain. Introns that interrupted codons are marked in red. In the cases in which the mutation's effect on the protein (except for splice site and long InDel mutations) had not been reported, we used MutationTaster software (http://www.mutationtaster.org) to predict amino acid changes. The red colored mutation indicates gain of function mutation.

Figure 2

Flowchart of the systematic search and study selection process.

Figure 3

Distribution of the available primary clinical diagnosis of the patients with ZAP-70 deficiency. EBV, Epstein-Barr virus; SCID, severe combined immunodeficiency; CID, combined immunodeficiency.

Figure 4

Type of first clinical manifestations in patients with ZAP-70 deficiency. The most common first presentations in ZAP-70 deficient patients reported were respiratory tract infections and dermatitis.