The Spectrum of GATA2 Deficiency Syndrome.

Inherited or de novo germline heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency; this results in a constellation of clinical features including infections with non-tuberculous mycobacterial, bacterial, fungal, and human papilloma virus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor which gives rise to B-lymphocytes, monocytes, Natural Killer (NK) cells and dendritic cells, leading to cytopenias of these lineages, and subsequent infections. The bone marrow failure is typically characterized by hypocellularity; dysplasia may be absent or subtle, but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and chronic myelomonocytic leukemia (CMML). The latter three malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency including: 1) why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2, 2) what are the genetic changes that lead to myeloid progression, 3) what causes the apparent genetic anticipation, and 4) what is the role of preemptive HSCT.