Abstract
Heterozygous familial or sporadic GATA2 mutations cause a multifaceted disorder, encompassing susceptibility to infection, pulmonary dysfunction, autoimmunity, lymphoedema and malignancy. Although often healthy in childhood, carriers of defective GATA2 alleles develop progressive loss of mononuclear cells (dendritic cells, monocytes, B and Natural Killer lymphocytes), elevated FLT3 ligand, and a 90% risk of clinical complications, including progression to myelodysplastic syndrome (MDS) by 60 years of age. Premature death may occur from childhood due to infection, pulmonary dysfunction, solid malignancy and MDS/acute myeloid leukaemia. GATA2 mutations include frameshifts, amino acid substitutions, insertions and deletions scattered throughout the gene but concentrated in the region encoding the two zinc finger domains. Mutations appear to cause haplo-insufficiency, which is known to impair haematopoietic stem cell survival in animal models. Management includes genetic counselling, prevention of infection, cancer surveillance, haematopoietic monitoring and, ultimately, stem cell transplantation upon the development of MDS or another life-threatening complication.
Highlights
myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) appears to be an equal risk with all types of GATA binding protein 2 (GATA2) mutation (Dickinson et al, 2014; Spinner et al, 2014)
These cohort studies highlight first, that carriers are haematologically normal at birth; second, that the phenotype of mononuclear cytopenia, or DCML deficiency, evolves over time; and third, that loss of mononuclear cells is a common feature of all patients with symptoms (Dickinson et al, 2014; Spinner et al, 2014)
It has been noted that few other conditions cause papillomatosis or generalized verrucosis to the same degree as GATA2 deficiency, namely Epidermodysplasia verruciformis (EV) warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome warts, immunodeficiency, lymphoedema and anogenital dysplasia (WILD) syndrome, DOCK8 deficiency syndrome and idiopathic CD4 lymphocytopenia (Vinh et al, 2010; West et al, 2014)
Summary
Heterozygous familial or sporadic GATA2 mutations cause a multifaceted disorder, encompassing susceptibility to infection, pulmonary dysfunction, autoimmunity, lymphoedema and malignancy. Management includes genetic counselling, prevention of infection, cancer surveillance, haematopoietic monitoring and, stem cell transplantation upon the development of MDS or another lifethreatening complication. GATA binding protein 2 (GATA2) is a key transcriptional regulator of haematopoiesis required for the development and maintenance of a healthy stem cell pool. GATA2 is required for HSC survival and self-renewal, interacting with a complex network of transcription factors that specify early lineage commitment, including SPI1 (PU.1), FLI1, TAL1 (SCL), LMO2 and RUNX1, among others (Dore et al, 2012; Beck et al, 2013; May et al, 2013).
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