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Newborn screening for primary immunodeficiencies

Jennifer M Puck, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS


The goal of newborn screening (NBS) is to detect treatable disorders that are threatening to life or long-term health before they become symptomatic [1]. Early treatment of these rare disorders may significantly reduce mortality and morbidity in affected patients, making screening programs using a high-throughput, low-cost screening test with high sensitivity and specificity an important and cost-effective public health measure. Severe combined immunodeficiency (SCID) meets these criteria for inclusion in NBS due to the availability of an effective assay for T cell receptor excision circles (TRECs), a biomarker for normal T cell development. Other primary immunodeficiencies (PIDs) in addition to SCID are potential targets for NBS if suitable biomarkers can be identified and put to use in screening assays [1,2].

The rationale and tests available for NBS for PIDs are reviewed here. The general principles of NBS, screening policies, testing, and follow-up are discussed in detail separately. (See "Newborn screening".)


PIDs are a group of disorders of the immune system that result in recurrent infections, or, in some instances, predominantly dysregulated immunity, that can significantly impact long-term health and life expectancy [3]. They are estimated to occur in as many as 1 in 1200 live births [4]. Close to 300 PIDs have been described, encompassing a wide range of clinical presentations and disease severity [3]. PIDs are classified according to the immunologic mechanisms and clinical presentations that result from the underlying defects, as well as the functional consequences of mutations upon their gene products. Adaptive immune defects predominantly affect antigen-driven processes. These defects include humoral immune deficiencies (due to impaired production of antibody by B cells) and combined immunodeficiencies (with impairments in both T and B cells). Innate immune disorders arise from impaired antigen-independent pathways and include defects in natural killer (NK) cell cytotoxicity, toll-like receptor (TLR) activation, phagocytosis, macrophage activation, and complement defects. More and more PIDs are associated with single gene defects. (See "Severe combined immunodeficiency (SCID): An overview" and "Combined immunodeficiencies", section on 'Overview' and "Primary humoral immunodeficiencies: An overview" and "Primary disorders of phagocytic function: An overview" and "Inherited disorders of the complement system" and "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

Treatment for PIDs depends upon the part(s) of the immune system affected and can include hematopoietic cell transplantation (HCT), immune globulin replacement therapy, and antimicrobial therapy to prevent or limit infections. Delay in diagnosis and treatment of PIDs leads to significant morbidity and sometimes early death from recurrent infections. Thus, early identification via newborn screening (NBS) should decrease the morbidity and mortality associated with these disorders. A retrospective study of 240 infants diagnosed with severe combined immunodeficiency (SCID) showed that overall survival (OS) at five years after transplant was similar amongst infants who received HCT at age <3.5 months (94 percent OS, 95% CI 85-98), at age >3.5 months while continuously infection free (90 percent OS, 95% CI 67-98), and even at age >3.5 months provided all infections had been treated and resolved prior to HCT (82 percent OS, 95% CI 70-90). In contrast, infants who were older than 3.5 months with active infection at time of transplant had greatly reduced OS (50 percent OS, 95% CI 39-61) [5]. These data further support the importance of NBS for SCID to allow early detection prior to the onset of infections. (See "Hematopoietic cell transplantation for primary immunodeficiency" and "Primary immunodeficiency: Overview of management" and "Immune globulin therapy in primary immunodeficiency" and "Gene therapy for primary immunodeficiency".)


The first group of PIDs targeted for newborn screening (NBS) was severe combined immunodeficiency (SCID). The term "SCID" encompasses a genetically heterogenous group of disorders characterized by profound impairment in T cell development and function with either primary or secondary defects in B cells (table 1). Infants with SCID are generally healthy at birth, protected by transplacentally acquired maternal immunoglobulin G (IgG) antibodies in the first few months of life. As this protection wanes, these infants develop severe and recurrent infections (including infections caused by live-virus vaccines given early in life), chronic diarrhea, and poor weight gain. Hematopoietic cell transplantation (HCT) has been shown to be an effective treatment for SCID, particularly if performed early in infancy, before the development of recurrent and increasingly severe infections. Infants with SCID without reconstitution of a functioning immune system usually die of overwhelming infection by one year of age. Only approximately 20 percent of infants with SCID have a family history that prompts early testing [6]. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations' and "Hematopoietic cell transplantation for primary immunodeficiency", section on 'Early identification'.)

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Literature review current through: Nov 2017. | This topic last updated: Jan 04, 2017.
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