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. Sharifinejad et al. Reported Patients With ZAP-70 Deficiency 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.

EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity

“…No significant outcome difference according to conditioning, donor type and age at transplant has been shown, so fully myeloablative conditioning may not be required in all PIRDs possibly with the exception of gain-of-function diseases. An increasing number of reports are published for other disorders including but not restricted to CTLA4 [ 88 , 89 ], LRBA [ 90 , 91 ], ZAP70 [ 92 , 93 ], and STAT1 gain-of-function [ 94 ].…”

Lymphocyte Disturbance in The [Asp521Asn] ZAP70 Mutation and An Overview of All Phenotype/Genotype

“…Distinct from the recent review summarized by Shari nedjad et al, 77 our study emphasized more on optimal treatment. In practice, all of the patients with ZAP70 mutations received regular immunoglobulin infusion and prophylactics for opportunistic infections.…”

“…46 In the strict sense, no relationship between genotype and phenotype existed as the recent review. 77 For Kaplan-Meier survival analysis, those receiving HSCT showed an obviously and signi cantly higher survival (p=0.0003) than without, but not in the other comparisons of opportunistic infections (p=0.2240), immune dysregulation (p=0.5268), and failure to thrive (p=0.5215). (Fig.…”

A boy with a novel homozygous ZAP70 mutation presenting with a dermatological phenotype and postnatal decrease in CD8+ T cells

“…Hypomorphic mutations also exist, having been described in five patients. These patients present with less severe symptoms compared to patients with complete loss but also exhibit low levels of poorly functioning CD8 + T cells 1,3 . Interestingly, Chan et al described a compound heterozygosity for loss‐and gain‐of‐function mutations, disrupting the autoinhibition of the protein, constituting a third form of mutations in ZAP70 deficiency.…”

“…The current definitive treatment of ZAP-70 deficiency is hematopoietic stem cell transplantation (HSCT). 1 To date, 52 patients with biallelic mutations in the ZAP70 gene have been described in the literature. 1,2 Herein, we report a patient with a novel missense mutation in the ZAP70 who presented with atypical skin lesions and a rapid decrease in CD8 + T-cell counts on immunological evaluations between 6 and 9 months of age.…”