Allogeneic Hematopoietic Stem Cell Transplant Restores Naïve T Cell Immune Reconstitution in Infants with SCID Phenotype due to EXTL3 Deficiency

Background EXTL3 deficiency is associated with a neuro-immuno-skeletal dysplasia syndrome due to defective heparan sulfate synthesis. Patients can present with a SCID phenotype from inability to generate early T cell progenitors in the bone marrow and impaired thymopoiesis due to defective thymic epithelial cell differentiation. There are limited data on the success of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with SCID phenotype due to EXTL3 deficiency. We hypothesized that allogeneic HSCT can restore naïve T cell immune reconstitution in patients with SCID phenotype due to EXTL3 deficiency despite defective thymopoiesis. Methods We report our single center retrospective analysis of two patients who underwent allogeneic HSCT for SCID phenotype due to EXTL3 deficiency. Results Two infants were referred to our center due to abnormal TRECs on newborn screening and were found to have T-, B+, NK+ SCID phenotype (Table 1). Both had skeletal dysplasia, and genetic testing showed biallelic mutations in EXTL3 gene (Table 1). Artificial thymic organoid differentiation assay was suggestive of a thymic defect in patient 1 (Figure 1). Patient 2 developed Omenn syndrome that required treatment with anti-thymocyte globulin. Additional clinical details and transplant characteristics are shown in Table 1. Both patients underwent unrelated donor cord blood transplant with reduced intensity conditioning that included fludarabine, melphalan, and thiotepa without serotherapy. Both tolerated conditioning well without excess toxicity. Patient 1 engrafted on day +14 and patient 2 on day +13 post-HSCT. Both engrafted with full donor chimerism and experienced engraftment syndrome with brief oxygen requirement. Patient 2 experienced grade I acute skin GVHD that was treated with topical steroids. None of the patients developed chronic GVHD. At last follow-up (3 years post-HSCT in patient 1 and 2 years post-HSCT in patient 2), both patients had excellent T cell and B cell immune reconstitution with normal CD4+ naïve T cell counts (Table 2). Both were off IgG replacement and demonstrated protective vaccine titers. Both patients continue to have significant neurodevelopmental delay. Table 1. Patient and transplant characteristics. Patient 1 Patient 2 Age at presentation 4 weeks 10 days Gender Female Male Race Caucasian African American Gene variant c.1006C>T, (p.Pro336Ser) c.1609C>T, (p.Arg537Cys) Heterozygous (Paternal) Heterozygous c.1040G>A, (p.Gly347Asp) c.2506A>G (p.Met836Val) Heterozygous (Maternal) Heterozygous Lymphocyte subsets CD3: 27, CD4:25, CD8:0, CD19: 1398, CD16/56: 170 cells/µL CD3: 16, CD4:0, CD8:11, CD19: 1409, CD16/56:467 cells/µL CD4 naïve T cells: 6% CD4 naïve T cells: NR Skeletal abnormalities Clinodactyly Platyspondyly, broadening of the tufts of the distal phalanges of the middle, ring, and small fingers Neurodevelopmental abnormalities Yes Yes Maternal engraftment No No Omen Syndrome No Yes Pre-transplant infections No Staphylococcus Aureus Bacteriemia Staphylococcus Epidermis Bacteriemia Transplant characteristics Age at transplant 3 months 5 months HLA match 10/10 HLA 8/10 HLA Stem cell source Cord Cord TNC count 49.5 x 10x7 TNC/kg 14.25 x 10x7 TNC/kg CD34 count 19.6 x 10x5 CD34/kg 12.7x10x5 CD34/kg Conditioning regimen* RIC RIC GVHD prophylaxis CSA/MMF CSA/MMF Neutrophil engraftment Day 14 Day 13 Platelet engraftment Day 40 Day 27 Transplant complications Engraftment Syndrome Yes Yes Acute GVHD No Yes, skin (mild) Chronic GVHD No No Infections Right upper lobe pneumonia Pseudomonas aeruginosa bacteriemia Seizure No Yes *RIC regimen: Fludarabine 1 mg/kg/dose IV for 5 day (days -8 to -4), Melphalan 4.7 mg/kg/dose once at day -3, Thiotepa 200 mg/m2/dose once at day -2. Figure 1. Artificial thymic organoid differentiation assay for patient 1. *Control: Cord Blood, CD34+. Table 2. Immune reconstitution at last follow-up post-transplant. Patient 1 Patient 2 (3 yrs. post HSCT) (2 yrs. post HSCT) Donor chimerism (%) 100% myeloid 100% donor 99% T cell Absolute CD3+ T cells (cells/mcL) 2653 3691 Absolute CD4+ T cells (cells/mcL) 1771 2251 Naïve CD4+ T cells (%) 68.2 69.2 Absolute CD4 naïve T cells 1204 1553 Absolute CD8+ T cells (cells/mcL) 707 987 Absolute NK cells (cells/mcL) 560 538 Absolute B cells (cells/mcL) 1063 1371 IgG (mg/dL) 728 974 IgM (mg/dL) 71.8 154 IgA (mg/dL) 66.3 166 Conclusion Our experience suggests that allogeneic HSCT is well tolerated, restores naïve T cell immune reconstitution, and is a potential curative approach for the SCID phenotype in EXTL3 deficiency despite defective thymopoiesis.

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