Unexplained thrombosis and profound monocytopenia in an adolescent: Delayed diagnosis of GATA2 haploinsufficiency

Abstract Introduction: GATA2 haploinsufficiency, or MonoMAC syndrome, is an autosomal dominant disorder characterized by monocytopenia and mycobacterial infections (MAC) in late childhood to early adulthood. Other phenotypes include Emberger syndrome, DCML (dendritic cell, monocyte, B, and natural killer [NK] lymphoid) deficiency, and a syndrome of familial myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). GATA2 is a transcription factor essential for hematopoietic stem cell development and lineage commitment, with deficiency encompassing a spectrum of overlapping hematologic, immunologic, vascular, and lymphatic abnormalities and clinical presentations (Calvo and Hickstein, 2023; PMID: 36455197). We present a unique case of an adolescent initially presenting with venous thrombosis concomitantly with (overlooked) profound monocytopenia, who was ultimately diagnosed with GATA2 haploinsufficiency, and referred for allogeneic stem cell transplant due to MDS development. Results: A 24-year-old Black man presented to the clinic for anticoagulation recommendations. After shoulder surgery at age 16, he developed thrombosis of the common left iliac and femoral veins with extension into the inferior vena cava (IVC), requiring thrombolytic therapy. He reported recurrent chlamydial infections with sexual activity, starting at age 16, but had no history of mycobacterial or viral infections, deafness, or lymphedema. Family history was negative for hematologic disorders. Complete blood count (CBC) was normal apart from persistent monocytopenia (absolute count zero), also present on a CBC from a decade earlier, prompting the workup for GATA2 deficiency. Decreased T-cells and profoundly decreased B- and NK-cells (both <1%) were observed on peripheral blood flow cytometry analysis. Bone marrow (BM) was hypocellular (40%), with a marked decrease in myeloid elements (>10% dysplastic). Megakaryocytes displayed dysmorphic morphology. There was no increase in blasts. BM cytogenetics showed gain of 1q in 7 of 20 cells karyotyped, and next-generation sequencing (NGS) by in-house and commercial myeloid disorder panels detected 2 pathogenic truncating somatic mutations in STAG2 (K887 [VAF 6%]; R1033 [13%]), all findings typically observed in GATA2 deficiency (Largeaud et al, 2023; 36727400). No GATA2 mutation was detected. Subsequently, a hereditary bone marrow failure (BMF) panel performed on peripheral blood and, later, skin fibroblasts identified a known heterozygous pathogenic GATA2 variant in the intron 5 enhancer region—NM_032638.5: c.1017+572C>T, (Hsu et al, 2013; 23502222), which corrupts an ETS binding motif—a GATA-2 region not typically covered by NGS myeloid disorder panels. Given the myelodysplastic BM changes (“Spectrum 1” disease, see Largeaud et al), 1q gain and STAG2 somatic mutations in the context of a germline GATA2 mutation, he was referred for stem cell transplant; he is at high risk of progression to AML. Cascade testing of his parents, and potentially his seven half-siblings, is ongoing (>50% of germline mutations are de novo). Conclusion: This case describes a delay in diagnosis of GATA2 haploinsufficiency despite the decade-long history of monocytopenia and his thrombosis management by a hematologist. MDS development during this time period illustrates the importance of early diagnosis (see Calvo and Hickstein, 2023). The thrombosis was attributed to shoulder surgery, but, in retrospect, extensive thrombosis in a healthy adolescent with a negative thrombophilia workup may have been due to a vascular abnormality and/or endothelial dysfunction related to the underlying GATA-2 deficiency. The somatic NGS myeloid disorders panel involving exon sequencing also failed to detect this GATA2 mutation, with a hereditary BMF panel required to identify a germline pathogenic variant involving intron 5, indicating the potential limitations of most commercial somatic NGS panels in ruling out GATA2 deficiency. While the immunodeficiency typically results in disseminated MAC, HPV, and fungal infections (Vinh et al, 2010;20040766), chlamydial infection is also controlled by T cells and monocytes, thus recurring chlamydial infections may be a novel marker of GATA-2 deficiency in this age group. In sum, GATA2 deficiency should be considered in young adults with unexplained thrombosis and monocytopenia. Importantly, subsequent cascade testing has the potential to diagnose other GATA2 deficient family members who may have covert MDS/AML.