A Large Cohort of RAG1/2-Deficient SCID Patients—Clinical, Immunological, and Prognostic Analysis

Noa Greenberg-Kushnir*, Yu Nee Lee, Amos J. Simon, Atar Lev, Nufar Marcus, Omar Abuzaitoun, Raz Somech, Tali Stauber

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Severe combined immunodeficiency (SCID) is a fatal disorder resulting from various genetic defects. In the Middle East, where consanguineous marriage is prevalent, autosomal recessive mutations in recombination-activating genes (RAG) are a leading cause of SCID. We present a large cohort of SCID patients due to RAG1 or RAG2 mutations. Methods: Twenty-six patients with RAG1 or RAG2 deficiency, diagnosed at Sheba Medical Center, were retrospectively investigated. Clinical presentation, immunologic phenotype, genetic analysis, treatment, and outcome were analyzed. Results: Majority of patients were referred from the Palestinian Authority. Most patients were males of Muslim Arab descent, 77% were born to consanguineous parents, and 65% had family history of immunodeficiency. Nearly all patients suffered from various infections before turning 2 months old, eight patients (31%) presented with Omenn and Omenn-like syndrome, and three patients (11%) had maternal engraftment. Notably, seven patients (27%) suffered from vaccine-derived infections, including a rare case of measles encephalitis. Nineteen patients underwent hematopoietic stem cell transplantation (HSCT) at a median age of 6 months, with a successful outcome for 72% of them. Genetic analysis revealed 11 different mutations (7 RAG2, 4 RAG1), two of them novel. Conclusions: Consanguineous marriages account for a genetic “founder effect.” SCID is a pediatric emergency that dictates immediate precautions and curative treatment with HSCT. Due to lack of newborn screening for SCID within the Palestinian population, most patients in this cohort were diagnosed upon clinical symptoms, which led to a delayed diagnosis, harmful administration of contra-indicated live vaccines, delay in HSCT, and poor outcome.

Original languageEnglish
Pages (from-to)211-222
Number of pages12
JournalJournal of Clinical Immunology
Volume40
Issue number1
DOIs
StatePublished - 1 Jan 2020

Funding

FundersFunder number
European Union’s Horizon 2020
Jeffrey Modell Foundation
Horizon 2020 Framework Programme755170

    Keywords

    • RAG1/RAG2 mutations
    • SCID
    • founder effect
    • live vaccines
    • newborn screening

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