Newborn screening for severe combined immunodeficiency and T-cell lymphopenia

Abstract

The development of a T cell receptor excision circle (TREC) assay utilizing dried blood spots (DBS) made possible universal newborn screening (NBS) for severe combined immunodeficiency (SCID) as a public health measure. Upon being flagged by an abnormal screening test in a SCID screening program, an infant can receive further diagnostic testing for SCID in the neonatal period, prior to onset of infectious complications, to permit immediate institution of protective measures and definitive, life-saving treatment to establish a functional immune system. SCID screening is now the accepted standard of care in state public health departments across the United States, and it is being adopted in many countries. It has proven effective, with infants having this otherwise inapparent but serious, rare disorder achieving survival and immune reconstitution. In addition to bringing to attention infants with the primary screening target diseases, typical SCID and leaky SCID (due to hypomorphic mutations in known SCID genes), the NBS assay for insufficient TRECs in DBS also reveals infants with non-SCID T lymphopenic conditions. Experience has accumulated regarding the range and limitations of diagnoses of newborns with low TRECs and low T cells. Previously unknown immune defects have been discovered, as well as conditions not formerly recognized to have low T cells in the neonatal period.

Keywords: T cell lymphopenia; T cell receptor excision circle; hematopoietic cell transplantation; newborn screening; primary immunodeficiency; severe combined immunodeficiency.

Figure 1.

Evolution of knowledge and patient care in primary immunodeficieny.

Figure 2.

Newborns screened for SCID in California showing number of infants at each screening stage (left) and proportion in neonatal intensive care unit (NICU) (right). Total infants screened included 91% cared for in a regular well-infant nursery, and 9% in a neonatal intensive care unit (NICU). Infants requiring a liquid blood sample tested after one positive or 2 incomplete TREC tests (53% NICU) were 0.17% of all births. Infants with fewer than 1,500 T cells/μL or <2% naïve CD3 CD4 CD45RA T helper cells (54% NICU) were 0.007% of all births (1 per 15,000).

Figure 3.

Genotypes of 50 SCID cases found by newborn screening in California, 2010–2017.

Figure 4.

Diagnoses of infants with T cell lymphopenia (TCL) detected by SCID newborn screening, including 50 with SCID (adapted from ref xx), 71 with a syndrome in which T cells may be insufficient, 25 with TCL secondary to other neonatal conditions, 33 with preterm birth alone, and 33 idiopathic. Forty percent of the 55 initially idiopathic cases were confirmed to have a syndrome after up to 1 year of follow-up. Of the remaining 33 infants 13 resolved or improved spontaneously over time. a For details see table 2. b Includes in utero exposure to maternal immunosuppressive medications (1 instance each of fingolimod, azathioprine), teratoma of the thymus