GATA 2 Deficiency: Focus on Immune System Impairment

Abstract

GATA2 deficiency is a disease with a broad spectrum of clinical presentation, ranging from lymphedema, deafness, pulmonary dysfunction to miscarriage and urogenital anomalies, but it is mainly recognized as an immune system and bone marrow disorder. It is caused by various heterozygous mutations in the GATA2 gene, encoding for a zinc finger transcription factor with a key role for the development and maintenance of a pool of hematopoietic stem cells; notably, most of these mutations arise de novo. Patients carrying a mutated allele usually develop a loss of some cell populations, such as B-cell, dendritic cell, natural killer cell, and monocytes, and are predisposed to disseminated human papilloma virus and mycobacterial infections. Also, these patients have a predisposition to myeloid neoplasms, including myelodysplastic syndromes, myeloproliferative neoplasms, chronic myelomonocytic leukaemia. The age of symptoms onset can vary greatly even also within the same family, ranging from early childhood to late adulthood; incidence increases by age and most frequently clinical presentation is between the second and third decade of life. Currently, haematopoietic stem cell transplantation represents the only curative treatment, restoring both the hematopoietic and immune system function.

GATA2 deficiency detected by newborn screening for SCID: A case report

“…The evolution of cytopenias in GATA2 deficiency syndrome has been described using symptomatic patients with DCML deficiency, and even though T cell cytopenias have been described, the profound and persistent T cell lymphopenia from birth in our patient is unusual and to our knowledge this early finding has not been described in GATA2 deficiency before (3,7,8). It is unclear if this presentation is simply a variable presentation of GATA2 deficiency, or if there are other genetic modifiers that may have affected these results.…”

“…Of the 6 GATA proteins, GATA1 and GATA2 play critical roles in hematopoiesis with GATA2 being a key transcriptional regulator required for the development and maintenance of a healthy stem cell pool (4,5). Hematological manifestations of GATA2 deficiency include a range of peripheral cytopenias of which the most common are profound cytopenias of B-cells, NK cells, and monocytes, that tend to be progressive with loss of bone marrow progenitor populations over time and a tendency toward clonal hematopoiesis (6)(7)(8).…”

The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia

“…Meggendorfer et al concluded that mutations in GATA2 , ASXL1 , IDH2 , RUNX1 , NRAS , SRSF2 , and ETV6 genes might predispose a transformation to leukemia [ 23 ]. It was observed that MDS cases with GATA2 mutation presented cytogenetic aberrations: the most frequent were chromosome 7 anomalies such as monosomy 7 and der (7) in 41% of investigated patients, followed by the gain of chromosome 8 (trisomy 8) in 15% of patients, while complex karyotype and deletion 5q were very rare or absent [ 68 ].…”

Genetic Predisposition to Hematologic Malignancies in Childhood and Adolescence

“…However, bone marrow dysfunction represents the hallmark of the disease, leading to recurrent infections (mainly atypical mycobacterial infections and recurrent HPV-related warts) and hematological malignancies. 47 – 49 Patients carry loss-of-functions mutations, involving mostly the second zinc finger domain and resulting in GATA2 haploinsufficiency. 50 GATA2 deficiency underlies 15% of advanced forms and 7% of all primary MDS in childhood.…”