IntroductionAdenosine deaminase–deficient severe combined immunodeficiency (ADA-SCID) is an autosomal recessive disorder comprising ∼15% of SCID cases. Newborn screening (NBS) relies on T cell receptor excision circle (TRECs) analysis, which may be normal at the time of testing. Once ADA-SCID is diagnosed, screening of family members is critical, as toxic metabolite accumulation leads to profound immunodeficiency, opportunistic infections, and multisystem organ dysfunction. We present an infant with a normal TRECs NBS who was diagnosed with ADA-SCID following post-mortem genetic testing of a deceased sibling.Case PresentationA previously healthy 2-month-old male presented with otitis media, oral thrush, and poor weight gain. TRECs NBS was normal. Family history was notable for an older brother who died at 2 years of age from fulminant hepatic failure attributed to hemophagocytic lymphohistiocytosis (HLH). Given this history, soluble IL-2 receptor levels were evaluated in our patient and were markedly elevated (4,274 pg/mL), prompting evaluation for familial HLH. Initial laboratory studies demonstrated mildly decreased absolute lymphocyte count, elevated ferritin, hypertriglyceridemia, and normal hepatic function (supplemental table 1). HLH genetic sequencing panel was negative.To clarify the diagnosis, post-mortem genetic testing of the sibling was performed and revealed compound heterozygous ADA variants: a pathogenic mutation, ADA1 c.632G>A (p.Arg211His), and a variant of uncertain significance, c.362+5G>C.At 4 months of age, our patient’s immunologic evaluation demonstrated worsening lymphopenia and eosinophilia (supplemental table 2). Flow cytometry showed declining CD4+ and CD8+ T cells, CD56+ natural killer (NK) cells, and CD19+ B cells over time (supplemental table 2). Genetic testing confirmed the same ADA variants in the patient associated with deficient ADA enzyme activity with elevated deoxyadenosine nucleotide levels (dAXP), confirming ADA-SCID (supplemental table 3).Treatment included intravenous immunoglobulin (IVIG), antimicrobial prophylaxis, and PEGylated recombinant ADA (rADA) enzyme replacement therapy (ERT). By 8 weeks, ADA activity normalized, dAXP levels decreased, and lymphocyte counts improved. The patient remains clinically stable while awaiting hematopoietic stem cell transplantation.ConclusionThis case underscores the importance of early recognition and a high index of suspicion for ADA-SCID, which may present with normal SCID NBS results. This case highlights the critical role of family genetic screening in enabling timely, life-saving intervention.Tabular data are included as downloadable supplement files.
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