No single underlying common phenotype has been described in the majority of GATA2 deficiency syndrome patients.r Clinical features are diverse and variable (see Clinical features of GATA2 deficiency syndrome by organ system), even within the same family.r Some individuals develop a severe multisystem disorder, while others are more mildly affected or asymptomatic (though the latter is rare).rrrrrr In general, penetrance increases with age.r Of those who develop myeloid malignancy, the median age at onset is 17 years (range 0–78 years).r
Previously, individuals with GATA2 deficiency syndrome were often diagnosed with a specific clinical phenotype, most commonly:
- Familial MDS and AML
- Emberger syndrome (primary lymphoedema with immunodeficiency and MDS/AML)
- MonoMAC syndrome (monocytopenia and mycobacterial infection)
- DCML deficiency (dendritic cell, monocyte, B-cell and natural killer cell deficiency)
These phenotypes overlap and the dominant features seen in an individual may vary over time, shifting them between phenotype groups. Furthermore, numerous other features may be present, hence GATA2 deficiency syndrome is more appropriate terminology.
Currently there is no agreed protocol for the management of GATA2 pathogenic variant carriers who have not developed MDS or AML. The recommendations in this protocol are based on expert expert opinion.rrr Consider referring to a research protocol where available.
Predictive testing for germline GATA2 variants
Somatic genetic rescue (SGR) can lead to loss of a familial GATA2 pathogenic variant in white blood cell DNA from peripheral blood. SGR has been reported in both affected and unaffected GATA2 pathogenic variant carriers.r Saliva and buccal cell specimens can be contaminated with white blood cells and are not accurate for diagnosis of a germline GATA2 pathogenic variant. Cultured skin fibroblasts from a skin punch biopsy, or DNA extracted from hair bulbs, are the preferred tissue specimens for germline GATA2 testing.
If haematopoietic stem cell transplantation (HSCT) is planned, genetic testing of relatives who are potential donors is recommended to prevent HSCT from a relative who has inherited the familial GATA2 pathogenic variant.
The age at which predictive testing is offered to unaffected children at risk of inheriting a GATA2 variant should be individualised, taking into account the family history, clinical implications and patient/family preference.r
Haematological malignancy/neoplasia
Acute lymphoblasic leukaemia has been reported in a small number of patientsrr however this may represent sporadic occurrence.r
Surveillance
Patients need to seek medical advice promptly if they develop recurrent infection, oedema, genital warts, hearing issues or any signs/symptoms of MDS/AML, including fatigue, infections, bleeding and skin changes.r
There is no evidence of benefit of surveillance by periodic FBE, but this is a low-risk procedure and has the potential to detect peripheral blood abnormalities prior to onset of obvious symptoms.rrr
Bone marrow biopsy has the potential to detect malignant transformation prior to the onset of symptoms. However, this is an invasive procedure, there is incomplete penetrance for haematological neoplasia (see Lifetime risk of cancer/haematological features) and there is lack of evidence for a beneficial effect of baseline and/or periodic bone marrow biopsy on neoplasia-related morbidity and mortality. Surveillance by bone marrow biopsy is NOT recommended outside a research protocol.
It is possible that asymptomatic carriers of germline GATA2 pathogenic variants develop detectable clonal haematopoiesis prior to transformation to MDS or leukaemia. If this does happen, there is the potential to use next generation sequencing to detect clonal haematopoiesis in cells from peripheral blood or bone marrow for the prospective identification of those at higher risk for evolution to MDS/AML. This is a theoretical proposition and is NOT recommended outside a research protocol.
Other approaches
There is no evidence to support prophylactic/pre-emptive stem cell transplantation in GATA2 pathogenic variant carriers who have not developed a haematological malignancy.
The only curative treatment for MDS is allogeneic hematopoietic stem cell transplantation (HSCT). This also has benefit for management of any associated immunodeficiency. However, the donor type, conditioning regimen and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the GATA2 deficiency syndrome haematological and immune phenotypes, is not known. Early data suggests the outcome of HSCT in paediatric MDS is independent of GATA2 germline status.r