Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

Abstract

Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/μL <2,500) was noted in 63% of the patients. Based on immunophenotypic pattern, majority of the cases were T−B− SCID (39%) followed by T−B+ SCID (28%). MHC class II deficiency accounted for 10.5% of our patient group. A total of 49 patients were molecularly characterized in this study and 32 novel variants were identified in our cohort. The spectrum of genetic defects in our cohort revealed a wide genetic heterogeneity with the major genetic cause being RAG1/2 gene defect (n = 12) followed by IL2RG (n = 9) and JAK3 defects (n = 9). Rare forms of SCID like Purine nucleoside phosphorylase (PNP) deficiency, reticular dysgenesis, DNA-Protein Kinase (DNA-PKcs) deficiency, six cases of MHC class II deficiency and two ZAP70 deficiency were also identified in our cohort. Fourteen percent of the defects still remained uncharacterized despite the application of next generation sequencing. With the exception of MHC class II deficiency and ZAP70 deficiency, all SCID patients had extremely low T cell receptor excision (TRECs) (<18 copies/μL).

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

“…CD4 + T cell deficiency was reported in 12.2% of the ZAP-70 deficient patients. However, one patient was reported to have elevated CD8+ level, which deviates from the usual immunologic findings for ZAP-70 deficiency (9). Hypogammaglobulinemia and hyper IgM phenotype were each noted in 3 (13%) patients (3,8,22,34,38,42).…”

“…Mutations in ZAP70 were identified initially in patients of Mennonite descent and subsequently in other ethnicities, including Hispanics, Japanese, Kurdish, Turkish, Portuguese, Caucasian, Mexican, Malagasy, and Iranian patients (3)(4)(5)(6)(7)(8)(9). World map of ZAP-70 deficient patients is available in Figure S1.…”

Application of Flow Cytometry in Primary Immunodeficiencies: Experience From India

“…In our experience with the immunological characterization of SCID patients, almost 65% of our B + SCID cohort had absent T cells. Hence, both CD127 and phospho-STAT5 assays had a limited utility in our study and we had to rely on genetic analysis to identify the defect (36). Exploiting the fact that CD132 is expressed on all the lymphocyte sub-populations, studying its expression on B cells helps rule out X-SCID.…”

Flow Cytometry for Diagnosis of Primary Immune Deficiencies—A Tertiary Center Experience From North India

“…When T cells are present in reduced or normal numbers in a suspected case of SCID or CID, we perform T cell subset analysis using CD3, CD4, CD8, CD45RA, and CD45RO antibodies to estimate the naïve and memory T cells. As we have been getting reasonable results with this antibody cocktail, we have not considered addition of CD62L for processing these samples (20).…”