Newborn TREC screening for SCID has identified infants with idiopathic T cell lymphopenia (TCL) with no identifiable genetic causes. We describe 2 first cousins who both presented with low TRECs and T cell lymphopenia without a common genetic cause.
Subject A, a 2-year-old male, was referred for low TRECs: 24 (0, 73, and 0). Flow cytometry at 2 weeks of age revealed decreased absolute CD3+ T cells: 1148 cells/µL (nl 2500-5500 cells/µL), CD4+ T cells: 977 cells/µL (nl 1600-4000 cells/µL), and CD8+ T cells: 216 cells/µL (nl 560-1700 cells/µL). At 6 months of age, Subject A developed hypogammaglobulinemia: IgG = 140 mg/dL (nl 217-904 mg/dL), IgM = 17 mg/dL (nl 19-192 mg/dL), and IgA = 6 mg/dL (nl 2-83 mg/dl).
Subject B, a 3-month-old female cousin (mother is the sister of Subject A’s father), was referred for absent TRECs of 0. Initial lymphocyte subsets at 2 weeks of age were CD3+ T cells: 771 cells/µL, absolute CD4+ T cells: 642 cells/µL, and CD8+ T cells: 138 cells/µL. She had normal IgG and IgM levels.
Both children had normal numbers of CD19+ B cells and CD16, 56+ NK cells, nl CBCs, and mitogen responses. Variants of unknown significance (VUS) identified on Invitae IEI panels included ANKZF1, POLD1, and TNFAIP3 in Subject A and TFRC in Subject B. There were no common VUSs, confirmed on whole-genome testing. Neither child had an NICU stay or birth trauma. They remain asymptomatic with no severe viral or bacterial infections.
Extensive genetic testing did not identify any underlying genetic cause for their lymphopenia. Presently, both infants are being studied at NIH for possible thymic-derived IEIs. Artificial thymic organoids (ATO) generating CD34+ cells with stromal cells expressing the Notch ligands DLL1 or DLL4 allow the generation of mature TCRαβ+ CD3+ T cells in culture, which could reliably discriminate hematopoietic versus thymic defects of lymphopoiesis in these children.
Idiopathic TCL in infants is often difficult to characterize. Thymus-derived IEIs and epigenetic mechanism may be responsible for some of these cases.
