The T cell receptor excision circle (TREC) assay is an effective neonatal screening tool for severe combined immunodeficiency (SCID), enabling early diagnosis and timely intervention. While genetic analysis often confirms a causal mutation for T cell lymphopenia, challenges arise when patients phenotypically present with SCID despite lacking an identifiable genetic etiology. This scenario necessitates a high index of suspicion and decision-making regarding hematopoietic stem cell transplantation (HSCT).
We present a 2-month-old female with a history of undetectable TREC levels (0,0,0) who presented with fever and confirmed influenza and coronavirus on viral swab. Initial lymphocyte phenotyping revealed severe CD4+, CD8+ T cell lymphopenia with very low B cells (supplemental table). Concern for maternal engraftment was suspected because of a markedly low absolute CD45RA number of 7 (nl = 1,200–5,300 cells/uL) and CD45RO of 84 (nl = 90–1,400 cells/uL). Whole-exon sequencing (WES) demonstrated a heterozygous autosomal recessive pathogenic mutation in the Ataxia-Telangiectasia mutated gene (ATM) (c.802C>T), with negative whole-genome sequencing, confirming that there was not a second ATM mutation. WES also identified a heterozygous pathogenic mutation in RNASEH2A (autosomal recessive Aicardi-Goutières syndrome). A variant of uncertain significance (VUS) was also present in autosomal recessive POLD2, which can cause non-severe combined immunodeficiency. Despite the absence of a confirmed SCID gene, worsening T cell lymphopenia led to the decision of HSCT at age eight months using an allogeneic, unrelated cord blood donor.
This case highlights that a definitive SCID phenotype, even in the absence of an identifiable genetic cause, warrants close management, including timely HSCT. Continued vigilance is crucial for preventing devastating infectious complications in patients with severe T cell lymphopenia, emphasizing the importance of clinical judgment when genetic findings are inconclusive.
