Infection and myelodysplasia: A case report of GATA2 deficiency in a South African patient

**Background:** Myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) typically occur sporadically due to acquired somatic mutations. However, inherited and de novo germline mutations are increasingly recognized as important drivers. Identifying patients with germline variants that predispose to MDS/AML requires recognition of unusual patterns of clinical features and organ dysfunction. Severe, persistent, or recurrent mycobacterial infections with peripheral blood cytopenia, in the absence of secondary immunodeficiency, should raise concern for an inborn error of immunity (IEI). GATA2 deficiency is a single disorder encompassing four previously separate clinical syndromes, with autosomal dominant inheritance that may be familial (62%) or de novo (38%).

**Methods:** This is a case report from Tygerberg Hospital, South Africa. The patient underwent serial bone marrow examinations (BME), karyotyping, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) using the Ion Torrent Oncomine Myeloid Research Assay on the Ion GeneStudio S5 System. Germline confirmation was performed via NGS on a skin biopsy. Family members were screened for the GATA2 variant.

**Key Results:** A 24-year-old mixed race, HIV-negative male presented with severe pancytopenia (WCC 0.90 × 10⁹/L, neutrophils 0.68 × 10⁹/L, lymphocytes 0.20 × 10⁹/L, monocytes 0.01 × 10⁹/L, hemoglobin 4.2 g/dL, platelets 46 × 10⁹/L, RPI 0.1). He had a history of TB lymphadenitis at age 11, deep vein thrombosis with persistent lymphoedema of the left leg, progressive sensorineural hearing loss from age 21, and extensive verrucae on both hands and feet. Initial BME showed a hypocellular marrow with trilineage dysplasia and multiple small granulomas; mycobacterial culture identified Mycobacterium intracellulare. Karyotype was normal and FISH was negative for del5q, del7q, del20q, trisomy 8, and loss of Y. Repeat BME after anti-mycobacterial therapy showed persistent trilineage dysplasia with normal karyotype, consistent with MDS-MLD. NGS revealed a loss-of-function GATA2 variant (c.1009C>T p.(R337*)) at 47.97% allele frequency in bone marrow and 48.85% in skin, confirming germline origin. Two subclonal STAG2 loss-of-function variants were also detected (c.832C>T p.(Q278*) at 3.29% and c.2290C>T p.(Q764*) at 12.77%). Parents tested negative for the GATA2 variant, confirming a de novo mutation. Lymphocyte subsets showed marked monocytopenia, profoundly reduced B-cells (6 cells/μL at presentation, 8 cells/μL at diagnosis), relatively preserved CD8 T-cells, and initially normal NK-cells that became low on repeat testing (123 cells/μL initially, 45 cells/μL at diagnosis). Immunoglobulin fractions were normal.

**Clinical Implications:** This is the first case of GATA2 deficiency described in South Africa. The case highlights several diagnostic challenges: MDS with a normal karyotype in patients with comorbidities or on drugs that cause non-malignant dysplasia; the need for persistent pancytopenia despite optimal NTM management to trigger further hematological investigation; and the critical role of NGS in establishing clonality and diagnosing predisposing germline conditions. MDS occurs in 70% of persons with GATA2 deficiency, with transformation to AML or CMML in 5.7%. Allo-HSCT remains the only curative option, and screening of family members is critical—the patient's HLA-identical sister tested negative for the GATA2 variant. Features of IEI and myeloid malignancy should prompt investigation for germline variants.