Abstract

Severe combined immunodeficiency (SCID) is fatal unless treated with hematopoietic stem cell transplant. Delay in diagnosis is common without newborn screening. Family history of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis. The aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID. From 2005 to 2016, 147 SCID patients were referred to the Asian Primary Immunodeficiency Network. Patients with genetic diagnosis, age at presentation (AP), and AD were selected for study. A total of 88 different SCID gene mutations were identified in 94 patients, including 49 IL2RG mutations, 12 RAG1 mutations, 8 RAG2 mutations, 7 JAK3 mutations, 4 DCLRE1C mutations, 4 IL7R mutations, 2 RFXANK mutations, and 2 ADA mutations. A total of 29 mutations were previously unreported. Eighty-three of the 94 patients fulfilled the selection criteria. Their median AD was 4 months, and the time to diagnosis was 2 months. The commonest SCID was X-linked (n = 57). A total of 29 patients had a positive FH. Candidiasis (n = 27) and bacillus Calmette-Guérin (BCG) vaccine infection (n = 19) were the commonest infections. The median age for candidiasis and BCG infection documented were 3 months and 4 months, respectively. The median absolute lymphocyte count (ALC) was 1.05 × 109/L with over 88% patients below 3 × 109/L. Positive FH was associated with earlier AP by 1 month (p = 0.002) and diagnosis by 2 months (p = 0.008), but not shorter time to diagnosis (p = 0.494). Candidiasis was associated with later AD by 2 months (p = 0.008) and longer time to diagnosis by 0.55 months (p = 0.003). BCG infections were not associated with age or time to diagnosis. FH was useful to aid earlier diagnosis but was overlooked by clinicians and not by parents. Similarly, typical clinical features of SCID were not recognized by clinicians to shorten the time to diagnosis. We suggest that lymphocyte subset should be performed for any infant with one or more of the following four clinical features: FH, candidiasis, BCG infections, and ALC below 3 × 109/L.

Highlights

  • Severe combined immunodeficiency (SCID) is a group of genetic diseases causing profound developmental and functional impairment of T cells, affecting cellular and humoral immunities

  • Patients typically have low absolute lymphocyte count (ALC). They have been classified by the number of Abbreviations: ADA, adenosine deaminase gene; ALC, absolute lymphocyte count; AD, age at diagnosis; AP, age at presentation; APIN, Asian Primary Immunodeficiency Network; BCG, bacillus Calmette–Guérin; CMV, cytomegalovirus; DCLRE1C, DNA cross-link repair enzyme 1C (Artemis); FH, family history of early infant death; FN3, fibronectin type-III; FTT, failure to thrive; HSCT, hematopoietic stem cell transplant; ICU, intensive care unit; IL-2 receptor gamma chain gene (IL2RG), IL-2 receptor gamma chain; IL7R, IL-7 receptor alpha chain; JAK 3, janus kinase 3; PCP, Pneumocystis jiroveci; PID, primary immunodeficiency; RAG1, recombinase activating gene 1; RAG2, recombinase activating gene 2; RFXANK, regulatory factor X associated ankyrin containing protein; SCID, severe combined immunodeficiency; TREC, T-cell receptor excision circle

  • We found family history of early infant death was associated with earlier AP and earlier AD but not shorter time to diagnosis

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Summary

Introduction

Severe combined immunodeficiency (SCID) is a group of genetic diseases causing profound developmental and functional impairment of T cells, affecting cellular and humoral immunities. Patients typically have low absolute lymphocyte count (ALC) They have been classified by the number of Abbreviations: ADA, adenosine deaminase gene; ALC, absolute lymphocyte count; AD, age at diagnosis; AP, age at presentation; APIN, Asian Primary Immunodeficiency Network; BCG, bacillus Calmette–Guérin; CMV, cytomegalovirus; DCLRE1C, DNA cross-link repair enzyme 1C (Artemis); FH, family history of early infant death; FN3, fibronectin type-III; FTT, failure to thrive; HSCT, hematopoietic stem cell transplant; ICU, intensive care unit; IL2RG, IL-2 receptor gamma chain; IL7R, IL-7 receptor alpha chain; JAK 3, janus kinase 3; PCP, Pneumocystis jiroveci; PID, primary immunodeficiency; RAG1, recombinase activating gene 1; RAG2, recombinase activating gene 2; RFXANK, regulatory factor X associated ankyrin containing protein; SCID, severe combined immunodeficiency; TREC, T-cell receptor excision circle. History of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis

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