Novel Compound Heterozygous Mutations in ZAP70 Leading to a SCID Phenotype with Normal Downstream In vitro Signaling
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LETTER TO EDITOR
Novel Compound Heterozygous Mutations in ZAP70 Leading to a SCID Phenotype with Normal Downstream In vitro Signaling Kelsey Kaman 1,2 & Monique Abrams 1 & Kerry Dobbs 3 & Luigi D. Notarangelo 3 & Ottavia M. Delmonte 3 & Boaz Palterer 4,5 & Sung-Yun Pai 6,7 & Alicia Johnston 1 Received: 3 March 2020 / Accepted: 5 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
To the Editor: ZAP70 is the zeta chain of the T cell receptor associated protein kinase 70 and is a member of the protein tyrosine kinase family. Upon engagement of the T cell receptor (TCR) by antigen presented on major histocompatibility (MHC) molecules, the Src family kinase, Lck, is activated and phosphorylates immune-receptor tyrosine based activation motifs (ITAMs) of the CD3K chain. Phosphorylated ITAMs promote the recruitment and activation of ZAP70. The ZAP70 SH2 domain interacts with phosphotyrosines of the CD3K chain leading to increased intracellular calcium, transcription of IL-2, and T cell activation [1]. In humans, mutations in ZAP70 lead to abnormal thymus development presenting with CD8 lymphopenia but normal CD4 T cell numbers associated with defective T cell receptor (TCR) signaling. Severe combined immunodeficiency is the most common phenotype reported; however, immune dysregulation, autoimmunity, malignancy, and late onset combined immunodeficiency have all been described [2]. Recent reports
* Kelsey Kaman [email protected] 1
Department of Pediatrics, UMMS-Baystate, Springfield, MA, USA
2
Department of Allergy and Immunology, Yale University, CT New Haven, USA
3
Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA
4
Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
5
Flow Cytometric Diagnostic Centre and Immunotherapy, Careggi University Hospital, Florence, Italy
6
Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA, USA
7
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
suggest the amount of residual ZAP70 protein expression may modulate the clinical phenotype [3]. Importantly, newborn screening for SCID with enumeration of T cell rearrangement excision circles (TRECs) has been unreliable in its ability to detect ZAP70 SCID [4]. We report a novel mutation in ZAP70 leading to SCID phenotype. The patient was born vaginally at term to nonconsanguineous parents. Her newborn screen was normal with TRECs of 325 copies/μL (normal > 52 copies/μL). At 2 months of age, she presented with cough and was diagnosed with respiratory syncytial virus (RSV) bronchiolitis by respiratory pathogen PCR panel (RPP) and briefly required oxygen by nasal cannula. At 4 months, she developed an erythematous, papular rash over her face, and extremities that was unresponsive to topical anti-fungal and steroid creams. Fungal scraping of the rash was negative. At 6 months, she presented with cough and respiratory distress. RPP was not performed.
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