Cytomegalovirus (CMV) infection and severe combined immunodeficiency (SCID) can both present with T cell lymphopenia in infancy complicating early diagnosis. We present a unique case of profound lymphopenia in a newborn initially attributed to CMV infection, later found to be a novel RAG–associated SCID based on evolving immunologic and genetic findings.
A full-term female infant was identified on Florida newborn screening (NBS) to have low T cell receptor excision circles (142 copies/μL) on day of life 2. Flow cytometry at 2 weeks of age confirmed profound T cell lymphopenia (CD3 122 cells/µL; CD45RO+ 20%) with low CD4 and CD8 counts. Notably, B cells, natural killer (NK) cells, and immunoglobulin (IgG, IgA, IgM) levels were within normal limits, contributing to a T-B+NK+ phenotype. Genetic studies with INVITAE SCID and combined immunodeficiency (CID) gene panels were negative. Chromosomal microarray detected a duplication at 15q13.1-q13.2 classified as a variant of uncertain significance (VUS), prompting whole-exome sequencing (WES), which was negative. At 1 month of age, she was admitted with fever and found to have CMV viremia (141,000 IU/mL). Brain imaging, ophthalmologic exam, and hearing screen showed no signs of congenital CMV. Valganciclovir was initiated; however, 2 weeks later, she required admission for intravenous ganciclovir induction following discovery of worsening titers (315,000 IU/mL). CMV genotyping demonstrated no UL97, UL54, or UL56 mutations. Lymphocyte proliferation testing demonstrated normal responses to anti-CD3 alone and anti-CD3 with IL-2 but decreased proliferation to anti-CD3 with anti-CD28 co-stimulation. CD3 counts improved over time (1,081 cells/µL at 1 month; 1,292 cells/µL at 2 months; 1,313 cells/µL at 3 months), along with decreasing viremia (1,790 IU/mL), suggesting CMV-related immune suppression. However, T cell abnormalities persisted. Despite increasing CD3, CD4 counts remained low (∼200 cells/µL). External evaluation at the National Institutes of Health (NIH) demonstrated a block in T cell development with absence of CD3+ TCRαβ+ cells and present but aberrant CD4+CD8+ double-positive cells, which lack CD3 expression and the typical CD1a++ CD7dim phenotype. External WES at NIH identified a heterozygous RAG1 variant (NM_000448 c.908C>A; p.P303H), raising concern for a novel form of autosomal recessive RAG-associated SCID. At 9 months of treatment with valganciclovir, CMV viral load is still present at 595 IU/mL, and the patient is currently admitted for repeat ganciclovir induction, bone marrow biopsy, TCR repertoire analysis, RAG protein analysis, and assessment for future hematopoietic stem cell transplantation. Of note, the patient’s clinical course has been complicated by Salmonella and Norovirus enteritis, multiple central line–associated bloodstream infections (CLABSIs) with Staphylococcus epidermidis, Serratia marcescens, Bacillus cereus, and Salmonella enterica, recurrent candidal skin infections, thrush, and an undifferentiated dermatitis, further supporting a diagnosis of primary immunodeficiency. She is otherwise currently on prophylaxis with immunoglobulin replacement therapy, azithromycin, and trimethoprim-sulfamethoxazole.
This case illustrates the diagnostic complexity in distinguishing CMV immune suppression from primary immunodeficiency and highlights the importance of longitudinal immune assessment. RAG defects impair V(D)J recombination, resulting in decreased T cell diversity and immune dysregulation. While congenital CMV can disrupt immune function, the persistence of T cell abnormalities despite viral control supports an underlying primary immunodeficiency.
