Low T cell receptor excision circles (TRECs) on newborn screen and severe T cell lymphopenia in a term newborn raise concern for severe combined immunodeficiency (SCID). Genetic polymorphisms in thiopurine methyltransferase (TPMT) can alter the metabolism of the purine analogue azathioprine to toxic metabolites, including 6-mercaptopurine, resulting in severe T cell apoptosis and deficiency. We present an infant with twice abnormal newborn screen for TRECs and severe lymphopenia resulting from in utero azathioprine exposure.
A 9-day-old term newborn female with twice abnormal TREC screen appeared well with normal physical examination. Initial lymphocyte phenotyping demonstrated T cell lymphopenia (CD3+ 322/μL), absent B cells, and low natural killer (NK) cells (CD16+/CD56+ 8/μL), suspicious of T-/B-/NK- SCID. IgM and IgA were absent, with normal IgG (907 mg/dL). ADA1 and purine nucleoside phosphorylase (PNP) enzyme activity were normal. Further T cell phenotyping revealed age-appropriate thymic T cell output (recent thymic emigrant T cells 71%) with predominance of naïve (80%) over memory (20%) CD4 T cells, which was not consistent with SCID, thymus aplasia, or maternal T cell engraftment. The mother reported a diagnosis of myasthenia gravis and was on azathioprine therapy during pregnancy. She had normal numbers of T cells (CD3+ 1354/μL), low B cells (CD19+ 75/μL) and low NK cells (CD16+/CD56+ 19/μL), and normal serum immunoglobulins with protective antibodies to Rubella (113.8 IU/mL). Infant pharmacogenetic testing showed the TPMT *3A/*3A genotype (poor azathioprine metabolizer) with confirmed low TPMT enzyme activity (<2.3 EU). Both parents carry the TPMT*3A genotype without respective maternal pharmacogenetic testing prior to starting azathioprine. Infant lymphocytes are repopulating in a manner consistent with a diagnosis of neonatal azathioprine toxicity (Figure 1) with mild T cell lymphopenia (CD3+1400/μL), normal B cells (CD19+ 1083/μL), and normal NK cells (CD16+/CD56+ 312/μL) at age 84 days with normal IgM and IgG.
Postnatal lymphocyte development in an infant with twice abnormal newborn screen for SCID as a result of in utero exposure to azathioprine (reference ranges).
Postnatal lymphocyte development in an infant with twice abnormal newborn screen for SCID as a result of in utero exposure to azathioprine (reference ranges).
This case underscores the importance of a detailed family and medication history for secondary causes of a SCID phenotype. Maternal TPMT genotyping and/or enzyme activity testing during pregnancy may inform about their infant’s risk of lymphopenia through transplacental azathioprine exposure.
