Delayed Diagnosis of Germline GATA2 Deficiency Following Severe Adolescent Iliocaval Thrombosis and Decade-Long Monocytopenia: Diagnostic and Testing Pitfalls.
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GATA2 haploinsufficiency is an autosomal dominant germline bone marrow disorder with heterogeneous manifestations, including cytopenias, recurrent infections, and progression to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Vascular complications, including venous thrombosis, are increasingly recognized. We present a male who developed extensive iliocaval thrombosis at age 16 after minor surgery and had persistent absolute monocytopenia, which remained unaddressed. He subsequently developed recurrent urogenital chlamydial infections and progressive cytopenias. Bone marrow evaluation revealed hypocellularity with dysmegakaryopoiesis and dysgranulopoiesis, consistent with hypocellular MDS; cytogenetics showed a gain of 1q with der(1; 21) (q10; q10). Comprehensive myeloid next-generation sequencing panel (that included GATA2) identified truncating STAG2, but no GATA2 coding mutations. Hereditary bone marrow failure testing of blood and skin fibroblasts, however, revealed a GATA2 intron 4 enhancer (+9.5Kb) variant, confirming GATA2 deficiency. He was referred for allogeneic hematopoietic stem cell transplant. During the pretransplant phase, anticoagulation was temporarily held for 3 days for central venous catheter placement, which resulted in renal infarction, indicating his ongoing high risk of thrombosis. This case highlights missed opportunities to diagnose GATA2 deficiency: the presence of persistent monocytopenia and the development of extensive venous thrombosis in an adolescent following minor surgery. In addition, it demonstrates the limitations of standard somatic exome-focused ('myeloid disorder') panels in detecting noncoding GATA2 germline variants. In addition, for patients on anticoagulation with a history of extensive thrombosis or considered to be at high risk of recurrent thrombosis, periprocedural bridging should be considered, after careful assessment of thrombotic and bleeding risks. Early recognition of GATA2 deficiency enables timely genetic confirmation, cascade testing of family members and risk-adapted strategies to prevent progression to AML, recurrent thrombosis, and infections.