PMC10159173_01
Peripheral blood smear, wright stain depicts moderate normocytic normochromic anemia with leukocytosis, and marked lymphocytosis composed of pleomorphic mature-looking lymphoid cells (A); many atypical forms showing marked nuclear irregularities with multilobated forms (flower-like cells) (B); and/or cytoplasmic projections/pseudopods (C).
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F1
Peripheral smear (Figure 1) showed moderate normocytic normochromic anemia with leukocytosis, significant eosinophilia, and marked lymphocytosis composed of pleomorphic mature-looking lymphoid cells (Figure 1A), with prominent atypical forms showing cytoplasmic projections/pseudopods (Figure 1B) and/or marked nuclear irregularities with multilobated forms (flower-like cells) (Figure 1C).
(A) Baseline flow cytometry plot gated on CD3+ T-cells to assess the expression of CD4 and CD8. Lower left quadrant indicates DNTs (including alphabeta and gammadelta T-cells). (B) Baseline flow cytometry plot gated on DNTs showing predominant alphabeta vs. gammadelta T-cell receptor expression. (C) Post-treatment flow cytometry plot gated on CD3+ T-cells to assess CD4 and CD8 expression. The huge population of DNT noted pretreatment in the lower left quadrant has almost completely disappeared. DNT, double-negative CD3+ T-cells.
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F2
Immunophenotyping for T-cell subsets (ALPS panel) performed at 6 weeks of age (Figure 2A,B) demonstrated a marked increase in CD4-CD8- alphabeta T-cells 23,429 cells/mcL, (NR 6-86 cells/mcL), representing 74.21% of total CD3+ T-cells (diagnostic criterion for ALPS >2.5%). Figure 2B, which was gated on the CD4-CD8- DNTs, confirmed that the DNTs were predominantly alphabeta-TCR-positive (95.75% of DNTs) rather than gammadelta-TCR-positive (4.17%). Total DNTs had reduced markedly from 77.51% of T-cells (NR 1.1%-4.0%) down to 9.98% (NR 3.1%-6.7%) (Figure 2C).
Schematic diagram of FAS protein. The structure of FAS protein is indicated. The pathogenic variant affects the death domain, consequently affecting the signal transduction pathway, which would normally involve recruitment of FADD and activation of pro-caspase 8 or 10. Diagram courtesy of Khadija Karim.
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F3
This variant affects the death domain, consequently affecting the signal transduction pathway, which normally involves the recruitment of FAS-associated death domain (FADD) and the activation of pro-caspase 8 or 10 (Figure 3).