An 8-day old female is referred to immunology clinic with an abnormal newborn screen reporting undetectable TRECs. Complete blood count (CBC) reported red blood cell macrocytosis for age, thrombocytopenia, and severe lymphopenia (Table 1). Lymphocyte immunophenotyping by flow cytometry showed markedly reduced naive T cells, low/absent B cells and decreased NK cells (Absent bright CD56 cells) consistent with SCID phenotype (Table 2). She was started on Ig replacement therapy (SCIG), antimicrobial prophylaxis with acyclovir, fluconazole, and Trimethoprim-Sulfamethoxazole at 1-month of age. Thrombocytopenia resolved by 2-weeks of age.
Her initial work up included molecular testing for SCID and T cell disorders (ADA, CD3, CD45, DCLREIC, FOXN1, IL2RG, IL7R, JAK3, LIG4, NHEJ1, ORA1, RAG1/2, RMRP, STAT5B, STIM1, TBX1, and ZAP70), telomere length measurement, and flow cytometry-based mitogen testing which were all normal. A limited exome that includes >4,800 genes (Trusight, Illumina) was performed and demonstrated a known heterozygous pathogenic variant in GATA2 (p.Thr354Met, c.1061C > T), which was confirmed by Sanger sequencing. Her pattern of lymphopenia of B cells and NK cells, followed by progressive monocytopenia for age, was consistent with GATA2 deficiency. Parental evaluation demonstrated that the mother harbored the same mutation, and even though, mother has not presented with any clinical manifestations of disease, she was noted to have 1.7% CD56 bright cells which is below published normal.
Complications during the first 8 months of life included medication induced elevated transaminases requiring discontinuation of fluconazole prophylaxis, chronic diarrhea with a negative infectious work up that self-resolved after 1 month, and an uncomplicated Klebsiella oxytoca urinary tract infection. Bone marrow aspirate and biopsy at 7 months of age revealed a mildly hypocellular marrow for age (80% cellularity) with no dysplasia, no excess blasts, negative FISH panel for MDS and normal cytogenetics. Serial monitoring of lymphocyte immunophenotyping continued to show severe T cell, B cell and NK cell cytopenias that fitted a phenotypic picture of severe combined immunodeficiency (Table 2). Since cytopenias did not recover and worsen over time (specifically T cells), the decision was made to proceed with hematopoietic stem cell transplant (HSCT) before she developed life threatening infections.
At 8 months of age, she received a matched unrelated donor bone marrow transplant (male, 34 y old, 10/10 HLA matched, CMV matched) following myeloablative conditioning with busulfan, fludarabine and equine anti-thymocyte globulin (ATG). She engrafted with 100% donor chimerism. She was able to be weaned off SCIG 7 months post-transplant and started vaccinations 2 months after SCIG was discontinued with evidence of seroconversion for vaccine induced antibodies for pneumococcus and Haemophilus influenzae type B. Immunosuppression was discontinued at 10 months post-transplant, and she was off prophylactic antimicrobials after 1 year.
Two and a half years after transplant she was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) that was found to be donor derived. She was treated with 4 drug induction chemotherapy per COG protocol AALL1131 and imatinib followed by consolidation with blinatumomab. She achieved complete remission. Two years and 9 months after her initial transplant, she received a second allogeneic HSCT, this time a haploidentical transplant using her father as a donor. The myeloablative conditioning regimen consisted of total body irradiation, thiotepa, cyclophosphamide, and ATG, with alphabeta T-cell and CD19 cell depletion as graft vs. host disease (GVHD) prophylaxis. She engrafted with 100% donor chimerism. She has mild, chronic skin GVHD but is currently 13 months post-second transplant and doing well (Figure 1). The patient's donor derived leukemia case has been reported elsewhere.