GATA2 deficiency
GATA2 deficiency | |
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Other names | GATA2 haploinsufficiency, GATA2 deficiency syndrome |
GATA2 deficiency is a grouping of several disorders caused by common defect, namely, familial or sporadic
The various presentations of GATA2 deficiency include: 1) Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell, Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC or MonoMAC/DCML); 2) Emberger syndrome; 3) familial myelodysplastic syndrome/acute myeloid leukemia (i.e. familial MDS/AML); 3) chronic myelomonocytic leukemia (i.e. CMML); and 4) other anomalies such as aplastic anemia, chronic neutropenia, and wide-ranging immunological defects.[2] Each of these presentations is characterized by a specific constellation of signs and symptoms but often includes signs and symptoms more characteristic of other GATA2 deficiency presentations. Furthermore, individuals with identical GATA2 gene mutations can exhibit very different presentations.[1][2][3][4]
Prior to 2011, MonoMAC and the Emberger syndrome were clinically defined as unrelated
Presentations
The presentations of GATA2 deficiency commonly fall into various categories with MonoMAC and Emberger syndrome in the past and sometimes even currently being considered as separate entities. In most cases, the age of onset and initial signs and symptoms are variable with each presentation often being accompanied by signs or symptoms more typical of other presentations. Nonetheless, most cases of the deficiency exhibit a combination of signs and symptoms that fit the following presentations.[citation needed]
MonoMAC
Individuals affected by MonoMAC commonly present in early adulthood affected by one or more of the
Emberger Syndrome
Emberger syndrome presents as early as infancy but more typically in childhood or early adulthood with
Familial MDS/AML
Familial MDS/AML is an inherited predisposition to develop MDS, i.e. a disorder characterized by the development of a genetically distinct subpopulation (i.e. clone) of bone marrow
Congenital neutropenia
Congenital neutropenia refers to an assorted group of diseases that share a common set of signs and symptoms, viz., neutropenia, i.e. a low circulating blood neutrophil count, increased susceptibility to infections, various organ dysfunctions, and an extraordinarily high risk of developing leukemia.[13] A small percentage of individuals with familial or sporadic GATA2 deficiency present in their childhood with asymptomatic mild neutropenia but no other discernible hematological abnormalities except perhaps monocytopenia and macrocytosis, i.e. enlarged red blood cells. This presentation often persists for years but commonly progresses to include thrombocytopenia, increases susceptibility to infections due to, e.g. atypical mycobacteria or human papillomavirus, dysfunction of non-hematological organs, MDS, and leukemia (primarily AML and less commonly CMML). It is estimated that by age 30, 60% of these individuals develop leukemia.[2][4][9][13] Some of these individuals have large deletion mutations that span the GATA2 along with nearby genes and exhibit in addition to hematological defects various developmental abnormalities, neurological abnormalities, and/or body dysmorphic disorders.[14]
Other presentations
GATA2 deficiency has been diagnosed in up to 10% of individuals presenting with
Rare cases of individuals with GATA2 deficiency may also present with extreme monocytosis (i.e. increases in circulating blood monocytes) or CMML, i.e. monocytosis plus the presence of abnormal (blasts) in the circulation and/or bone marrow. GATA2 deficient individuals who develop CMML often exhibit mutations in one of their ASXL1 genes. Since mutations in this gene are associated with CMML independently of GATA2 mutations, ASXL1 mutations may promote the development of CMML in GATA2 deficiency.[1][2][15]
Symptoms
The age of onset of the GATA2 deficiency is variable with rare individuals showing first signs or symptoms in their infancy and others showing first symptoms or signs at almost any time thereafter including their later years. Rare individuals with inactivating GATA2 mutations may never develop symptoms, i.e. the disorder has a very high but nonetheless incomplete degree of penetrance.[7][16][8] This variability can occur between members of the same family who are documented to have the same GATA2 mutation.[17] The many signs and symptoms that are the direct or indirect consequences of GATA2 deficiency organized based on the types of involvement are:[1][16][18][8][5][6]
- Hematologic: chronic neutropenia, monocytopenia, monocytosis (rarely), thrombocytopenia (which unlike other hematologic findings is most often due to autoimmunity), bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, case reports of chronic lymphocytic leukemia and large granular lymphocytic leukemia.
- Lymphatic: lymphedema, i.e. fluid retention and tissue swelling caused by a compromised lymphatic system of the lower extremities (often complicated by deep vein thrombosis and cellulitis), lymphedema in other sites such as the face or testes (i.e. hydrocele).
- Immunologic: Increased susceptibility to infections caused by Herpes simplex, Varicella zoster virus, Epstein–Barr virus, cytomegalovirus, Molluscum contagiosum virus, nontuberculous mycobacteria, other bacteria, various aspergillus fungus species, various Candida fungus species, and histoplasma capsulatum;
- Tumors: Increased incidence of nasopharynx cancer, T cell non-Hodgkin lymphoma) benign and malignant tumors.
- Cancers: Increased incidence of pancreas cancer, kidney cancer, and breast cancer.
- primary biliary cirrhosis, aggressive multiple sclerosis.
- Lung: pulmonary artery hypertension; pulmonary ventilation and diffusion defects as defined by pulmonary function testing that may lead to respiratory failure.
- Neuorlogic: Sensorineural hearing loss mainly for high frequencies.
- Heart: Endocarditis (may reflect GATA2 deficiency in the endocardium and/or impaired overlap with GATA4 function, which is involved in the embryonic development of this organ).
- Thyroid gland: Idiopathic (i.e. unknown cause) hypothyroidism.
- Reproductive: High rate of miscarriage.
- .
- chronic headache.
Genetics
GATA2 transcription factor
The GATA2 transcription factor contains two
GATA2 binds to a specific nucleic acid sequence viz., (T/A(GATA)A/G), on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. However, there are thousands of sites in human DNA with this nucleotide sequence but, for unknown reasons, GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with GATA2 binding or even displace the GATA2 that is already bound to these sites. For example, displacement of GATA2 bond to this sequence by the GATA1 transcription factor appears important for the normal development of some types of hematological stem cells. This displacement phenomenon is termed the "GATA switch". In all events, the actions of GATA2 in regulating its target genes is extremely complex and not fully understood.[1][19][20][21]
GATA2 gene mutations
Inactivating mutations in the GATA2 gene are the primary cause of GATA2 deficiency disorders. This gene is a member of the evolutionarily conserved
The GATA2 gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located in intron 4. This site, termed the 9.5 kb enhancer, is located 9.5 kilobases (i.e. kb) down-stream from the gene's transcript initiation site and is a critically important enhancer of the gene's expression.[19] Regulation of GATA2 expression is highly complex. For example, in hematological stem cells, GATA2 transcription factor itself binds to one of these sites and in doing so is part of functionally important positive feedback autoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production of Interleukin 1 beta and CXCL2 which act indirectly to simulate GATA2 expression. In an example of a negative feedback circuit, the GATA2 transcription factor indirectly causes activation of the G protein-coupled receptor, GPR65, which then acts, also indirectly, to repress GATA2 gene expression.[19][20] In a second example of negative feed-back, GATA2 transcription factor stimulates the expression of the GATA1 transcription factor which in turn can displace GATA2 transcription factor from its gene-stimulating binding sites thereby limiting GATA2's actions (see GATA2 switch in "GATA2 transcription factor" section).[21]
The human GATA2 gene is
Scores of different types of inactivating GATA mutations have been associated with GATA2 deficiency; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the GATA2 transcription factor's ZF1, ZF2, and 9.5 kb sites. Rare cases of GATA2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of GATA mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances.[1][16]
Non-mutational GATA2 deficiency
Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parental GATA2 gene was not mutated but silenced by hypermethylation of its gene promoter. Further studies are required to define the involvement of this hypermethylation-induced form of GATA2 deficiency in other disorders as well to integrate it into the diagnostic category of GATA2 deficiency.[15]
Other genetic abnormalities
GATA2 deficiency disorders are variably associated with secondary genetic abnormalities.
Pathophysiology
Blood defects
Deletion of both Gata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in the
MonoMAC-affected individuals exhibit reduced levels of
Immunologic defects
The depletion of hematologic cells, particularly
Lymphedema
The GATA2 transcription factor contributes to controlling the expression of two genes, PROX1 and FOXC2, which are required for the proper development of the lymphatic system, particularly lymph vessel valves. It is proposed that GATA2 deficiency causes a failure to develop competent valves and/or vessels in the lymphatic system and thereby leads to lymphedema.[2]
Hearing loss
GATA2 deficiency-induced abnormalities in the lymphatic system are also proposed to be responsible for a failure in generating the
Other defects
The pathophysiology behind the other defects associated with GATA2 deficiency such as hypothyroidism, endocarditis, pulmonary alveolar proteinosis; cryptogenic organizing pneumonia-like disease, pulmonary hypertension, pulmonary ventilator and diffusion defects, miscarriages, etc., is as yet undefined. It is possible that many of these other defects are secondary, i.e. associated with GATA2 deficiency but not a direct result of low cellular levels of the GATA2 transcription factor.[citation needed]
Diagnosis
Individuals with GATA2 deficiency commonly exhibit abnormalities in their
Treatment
The various interventions recommended for GATA2 deficiency fall into three categories: family counseling, prevention of the disease's many complications, and bone marrow transplantation in an effort to restore GATA2-sufficient stem cells. However, due to the uncommonness of, and only recent appreciation for, the disease, standard phase 2 clinical trials to establish the efficacy of a drug(s), and/or non-drug treatment regiments against an appropriate placebo treatment regimen have not been reported.[citation needed]
Family counseling
Family members of an individual(s) diagnosed with an inactivating GATA2 gene mutation should be told of their chances of having this mutation, advised of the consequences of this mutation, recommended to be tested for the mutation, warned that they are not suitable donors for any GATA2 deficient individual, and offered long term follow up of their mutation.[1][2][19][15][29][30]
Prevention of complications
Recommendations for individuals exhibiting susceptibility to the infectious complications of GATA2 deficiency (e.g. MonoMAC-affected individuals) include: early vaccination for papillomavirus, early vaccination or prophylaxis drug treatment for nontuberculosus mycobacteria, and, perhaps, prophylaxis drug treatment (e.g.
Bone marrow transplantation
Many authorities currently recommend GATA2 deficiency be treated by a moderately but not maximally aggressive
Clinical trials
Many reports on the recommended treatment of GATA2 deficiency follow an NIH clinical trial termed "A Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant regimen for Patients With GATA2 Mutations". This trial used a regimen of medication (
Prognosis
Overall survival in a NIH study using a modest conditioning regimen followed by hematologic stem cell transplantation in GATA2 deficient patients affected by immune deficiencies was 54% at 4 years; GATA2 deficient children transplanted for MDS with monosomy 7 experienced a 5-year survival of 68%.[19][2]
History
In 2011, all cases of the previously described disorders of Emberger syndrome[7] and MonoMAC[34] as well as some cases of the previously described disorder of familial MDS/AML[35] were discovered to be due to inactivating mutations in the GATA2 gene. Subsequently, numerous studies discovered that a significant percentage of many other well-known hematological, immunological, autoimmune, and infectious diseases were associated with, and apparently due to, inactivating mutations in the GATA2 gene.[1][2]
References
- ^ PMID 28179280.
- ^ PMID 28643018.
- PMID 27248996.
- ^ PMID 24467820.
- ^ PMID 23728141.
- ^ S2CID 29935351.
- ^ S2CID 23449974.
- ^ S2CID 205312771.
- ^ PMID 25619630.
- ^ PMID 29438960.
- ^ PMID 27913534.
- PMID 29156196.
- ^ S2CID 1477026.
- PMID 29296959.
- ^ PMID 25397911.
- ^ PMID 24227816.
- PMID 28271814.
- ^ S2CID 3557136.
- ^ PMID 28637621.
- ^ PMID 28179282.
- ^ PMID 27235756.
- ^ PMID 23048181.
- ^ "GATA2 GATA binding protein 2 [Homo sapiens (human)] - Gene - NCBI".
- PMID 23736028.
- PMID 26017341.
- PMID 29278534.
- PMID 21242295.
- PMID 24638828.
- ^ PMID 25659730.
- ^ S2CID 19080505.
- PMID 27913495.
- ^ m. d, Dennis Hickstein (4 March 2020). "Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant for Patients with GATA2 Mutations".
- ^ "Allogeneic Hematopoietic Stem Cell Transplant for Patients with Mutations in GATA2 or the MonoMAC Syndrome". 20 May 2021.
- PMID 21765025.
- PMID 21892162.