Baby’s First Test: Importance of the Newborn Screen in the Diagnosis of SCID
Year: 2025
Type: article
Study design: Case Report
Abstract: Introduction Severe combined immunodeficiency (SCID) is defined as the inability of hematopoietic stem cells to differentiate into mature T cells, with or without B and natural killer (NK) cells. The most common genes involved include IL2RG, RAG1/RAG2, and ADA. The estimated incidence of SCID in the United States is 1 in 58,000 live births, but with the inclusion of SCID on the newborn screen (NBS), initiated between 2010 and 2018, survival has improved significantly through early identification and intervention. If intervention is performed before 3.5 months of age, survival increases to 94% compared with after 3.5 months of age with a survival rate of 70%. Case Presentation A 7-month-old female was admitted for acute respiratory failure secondary to bocavirus infection. The development of leukopenia, deteriorating clinical status, and lack of a completed NBS prompted a workup for an inborn error of immunity. Quantitative immunoglobulins were undetectable with low lymphocyte counts (Table 1). Flow cytometry showed markedly decreased B cells and T cells but retained NK cells, consistent with T-B-NK+SCID and concerning for RAG1-mutated SCID. A genetic panel revealed two pathogenic variants in RAG1:(c.1682G>A, a missense variant, and c.2487_2488delinsTT, a nonsense variant) (Table 2), confirming as autosomal recessive SCID. With improvement of respiratory status, intravenous immunoglobulin (IVIG) and anti-fungal and Mycobacterium avium complex prophylaxis were initiated. She continues monthly IVIG, prophylactic antibiotics and antifungals, and clinical monitoring while waiting for allogeneic hematopoietic stem cell transplant (HSCT). A pretransplant chest computed tomography scan revealed pulmonary nodules. At one year of age, she awaits HSCT, delayed for treatment of presumed fungal infection. Table 1.Lymphocyte count.Absolute Count (mm3)Reference Range7 (mm3)Percentage (%) of total lymphocytes (unless otherwise noted)Absolute Lymphocyte Count2643,400 - 9,000CD31401,900 - 5,90053.1CD41221,400 - 4,30046% of CD3CD810500 - 1,7003.8% of CD3CD19<1610 - 2,6000.05CD16/56119160 - 95045.2CD45RA of CD46396-3,1115.1% of CD4CD45RA of CD82264-1,42114.9% of CD8CD3 RA/RO0.1Table 2.RAG1 variants description.Variant 1Variant 2Sequence Changec.1682G>Ac.2487_2488delinsTTAmino Acid Changep.Arg561Hisp.Arg829_Lys830delinsSer*ClassificationPathogenicPathogenicZygosityHeterozygousHeterozygousType of VariantMissenseNon-senseGnomAD Frequency0.003%AbsentClinVar5 entries- Likely pathogenic/pathogenic (Variation ID: 13143)5 entries- pathogenic (Variation ID: 1034220)Experimental StudiesShown affects RAG1 functionNot applicableOther Evidence- Observed in other individuals with SCID8,10Observed in other individuals with SCID- Other variants that disrupt p.Arg561 amino acid residue have been determined pathogenic Discussion Newborn screening would likely have prompted earlier diagnosis and treatment of this patient, including reverse isolation, antimicrobial prophylaxis, and earlier preparation for transplant. This patient’s survival and long-term immune reconstitution may be impaired given that HSCT was not able to be performed before 3.5 months of age. Conclusion This case demonstrates the necessity of newborn screening, prompt confirmatory testing, including genetic panels, immune function testing, and HSCT in the diagnosis and management of SCID. With public skepticism of medical interventions rising, it emphasizes advocating for continued education and utilization of the NBS among providers and the public.
Source: Journal of Human Immunity
Authors: Olivia Hernadez, Victoria Bartlett, Shelagh Browne, Kristen Corey, David Gass, Chad McCall, Lyndsay Molinari, Elizabeth Baker
Institution: Levine Children's Hospital
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4409786219