Germline GATA2 Mutation and Bone Marrow Failure

Abstract

GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.

Transcription factor mutations as a cause of familial myeloid neoplasms

“…Another enigmatic feature of GATA-2 deficiency syndrome is the highly variable time of symptom onset (71). While symptoms can present in young children, adults can be asymptomatic, roid precursors, GATA-2 induces Gata1 and Kit transcription (50).…”

GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner

“…In 2011, germline heterozygous loss‐of‐function mutations in GATA2 causing haploinsufficiency were identified as the cause of a complex haematological and immunodeficiency phenotype (Dickinson et al , ; Hahn et al ., ; Hsu et al , ; Ostergaard et al , ). At present, GATA2 deficiency is increasingly thought of as a bone marrow failure state akin to aplastic anaemia based on a progressive depletion of the HSC pool (McReynolds et al , ). Patients develop a characteristic combination of cytopenias in monocytes, NK cells, DCs and B cells, resulting in increased susceptibility to severe bacterial, viral and fungal infections, particularly with human papilloma virus (HPV) and non‐tuberculous mycobacteria (NTM).…”

“…Although recent advances have led to a better knowledge of this syndrome, many issues still need to be addressed (McReynolds et al , ). Here, we discuss the challenges encountered in clinical practice regarding diagnosis and allo‐HSCT of GATA2‐deficient patients, based on our experience with three cases diagnosed at our hospital.…”

“…In 2011, germline heterozygous loss-offunction mutations in GATA2 causing haploinsufficiency were identified as the cause of a complex haematological and immunodeficiency phenotype (Dickinson et al, 2011;Hahn et al, 2011;Hsu et al, 2011;Ostergaard et al, 2011). At present, GATA2 deficiency is increasingly thought of as a bone marrow failure state akin to aplastic anaemia based on a progressive depletion of the HSC pool (McReynolds et al, 2018 (Spinner et al, 2014). Comparable to other primary immunodeficiencies caused by haploinsufficient genes, there is no consistent phenotype-genotype correlation (Bogaert et al, 2018).…”

“…The only curative treatment is allogeneic HSC transplantation (allo-HSCT), which can reverse the haematological, immunological and pulmonary manifestations (Parta et al, 2018). Although recent advances have led to a better knowledge of this syndrome, many issues still need to be addressed (McReynolds et al, 2018). Here, we discuss the challenges encountered in clinical practice regarding diagnosis and allo-HSCT of GATA2-deficient patients, based on our experience with three cases diagnosed at our hospital.…”