GATA2 Deficiency Presenting with Severe Immune Dysregulation

BackgroundGATA2 deficiency results from heterozygous pathogenic variants in the GATA2 gene, which encodes a zinc-finger transcription factor essential for hematopoietic stem and progenitor cell development. It is a highly variable inborn error of immunity characterized by monocytopenia, B and natural killer (NK) cell lymphopenia, susceptibility to infections, increased risk of myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), and pulmonary alveolar proteinosis. Autoimmune and inflammatory manifestations are increasingly recognized and include vasculitis, Sweet’s syndrome, ankylosing spondylitis, seronegative erosive rheumatoid arthritis, and lupus-like rashes, among others. However, lupus nephritis has not been clearly documented in association with GATA2 deficiency.Case PresentationA 25-year-old male was referred to immunology for a history of multifaceted immune dysregulation, including systemic lupus erythematosus (SLE), severe atopic dermatitis, asthma, and necrotizing pancreatitis. The SLE was diagnosed at age 17, and he developed biopsy-proven class IV lupus nephritis that progressed to end-stage renal disease requiring hemodialysis. His disease course has been further complicated by autoimmune hemolytic anemia, thrombocytopenia, pleural effusions, and suspected pericarditis. Bone marrow aspirate was punctio sicca, limiting assessment for dysplasia, and biopsy was moderately hypocellular with bony changes associated with renal osteodystrophy, and no evidence of increased blasts. He has received extensive immunosuppression with tacrolimus, cyclophosphamide, mycophenolate mofetil, rituximab, azathioprine, and corticosteroids. Despite these therapies, his SLE remains poorly controlled.The patient’s infectious history was notable for serious infections that occurred during periods of immunosuppression: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, Staphylococcus epidermidis endocarditis, Candida parapsilosis fungemia, C. difficile colitis, and shingles reactivation. Immune investigations revealed lymphopenia across all subsets with complete B cell absence despite discontinuing rituximab seven years prior. An immune and cytopenia gene panel identified a heterozygous pathogenic missense variant in GATA2 (NM_032638.5: c.1193G>A, p.(Arg398Gln)). Our patient lacks hallmark features of GATA2 deficiency: no monocytopenia, pulmonary alveolar proteinosis, or lymphedema.ConclusionThis case expands the recognized variability of GATA2 deficiency, showing that severe autoimmune or atopic manifestations may predominate even when hallmark features are absent. Although GATA2 deficiency is an unlikely explanation for most cases of SLE, it may be worth considering in refractory or atypical presentations, especially those marked by unexplained lymphopenia or other deficits that prompt evaluation for underlying inborn errors of immunity.