Ten Years of Newborn Screening for Severe Combined Immunodeficiency (SCID) in Massachusetts

Abstract

Background: Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots.

Objective: We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019).

Methods: TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated.

Results: NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment.

Conclusions: Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naïve T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.

Keywords: Athymia; Hematopoietic cell transplant (HCT); Newborn screening (NBS); Prematurity; SCID; TREC.

Figure 1.

Referral status for all infants evaluated by SCID NBS.

Figure 2.

TREC values by gestation age in 14,373 infants tested over a 3-month period.

Figure 3.

Underlying cause of T cell lymphopenia diagnosed in infants with abnormal NBS.

Figure 4.

A. Referral protocol based on absolute CD3 T cell count (CD3 abs) and %CD45RA⁺ (naïve) CD4 T and CD8 T cells. Patients were referred to immunology for CD3 abs < 2500 cells/mcL or naïve percentage of CD4 or CD8 T cells <50%. B-F. Absolute T cell counts and naïve CD4+ T cell percentages for patients with SCID/CID (B), thymic defects due to DiGeorge Syndrome or CHARGE syndrome (C), critical congenital heart disease (CCHD) (D), prematurity (born at < 37 weeks gestational age) (E), and patients with idiopathic T cell lymphopenia with normal in vitro T cell proliferation and no evidence of opportunistic infection or antibody deficiency (F). Dotted lines indicate cutoffs for CD3 abs and naïve CD4 T cells of 2500 cell/mcL and 50%, respectively. *Two ATM patients had nearly identical abs CD3 and % naïve CD4 T cells.