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GATA2 Deficiency
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
As GATA2 deficiency covers several previously unrelated disorders that all contain mutations in the transcription factor gene GATA2, its clinical presentations are not surprisingly diverse, including: MDS/AML often associated with secondary mutations, median onset age of 30 years, occurring in 30%–50% of cases, lifetime risk of 90%.Warts, severe viral infection (human papilloma virus, herpesviruses) present in 60%–70% of cases, 10%–20% cases due to disseminated CMV, EBV, or VZV.Pulmonary alveolar proteinosis or decreased lung function (loss of volume or diffusion) accounting for 18% proven PAP, usually GM-CSF antibody negative; 10% pulmonary artery hypertension (PAH), 50% abnormal PFT, 14% pneumonia.Mycobacterial or fungal infection representing 20%–50% non-tuberculous mycobacterial infection (NTM), 16% aspergillosis, 9% histoplasmosis.Recurrent upper respiratory tract infection (otitis, sinusitis; 10%–20% of cases); autoimmune manifestation (panniculitis, arthritis, lupus-like hypothyroidism, hepatitis; accounting for 30%–50% panniculitis).Solid tumors (HPV-related breast cancer, EBV+ mesenchymal skin cancer; representing 20%–35% intra-epithelial neoplasia, 22% of breast cancer in women >35 years, 10% skin cancer.Lymphedema (11%–20% of childhood or adolescent case); thrombosis (DVT, PE, catheter-related; 25% risk).Congenital deafness responsible for 20% abnormal audiograms.Preterm labor (maternal trait, 33% of cases) (Figures 74.1 and 74.2) [21–23].
GATA2-related myeloid neoplasms in pediatrics: where do we stand?
Published in Pediatric Hematology and Oncology, 2022
Manuela Spadea, Paola Quarello, Francesco Saglio, Lucia Pedace, Franca Fagioli
Last decade has witnessed an increased awareness of non-syndromic familial MDS/AML predisposition syndromes1 to the point that has led to these syndromes being considered as a separate category in the revised 2016 WHO classification of myeloid neoplasms.2 One of the most frequent germline predisposition syndromes involves the gene GATA2. Its first description dates back 2011.3 GATA2 encodes a zinc-finger (ZF) transcription factor expressed in hematopoietic stem cells and various hematopoietic progenitor cells in humans. Its major role in early hematopoiesis4 is attained by cooperating in a complex network of transcription factors in a dose-dependent manner.5 The GATA2 germline mutational landscape involves truncating mutations presumably resulting in loss of the second ZF (ZF2), missense mutations within ZF2, noncoding variants in the +9.5-kb regulatory region of GATA2, mutations resulting in abnormal mRNA splicing6 and a recently described in-frame insertion mutation.7 One-third of the mutations are inherited from a parent, and as many as two-thirds occurs de novo.
Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia
Published in Expert Review of Hematology, 2020
Mackenzie Bloom, Jamie L. Maciaszek, Mary Egan Clark, Ching-Hon Pui, Kim E. Nichols
A second challenge relates to determining the functional relevance of any identified germline variants. Although in silico approaches are commonly used to assist with this process, these approaches do not always accurately predict the true impact of germline variants on the function(s) of the encoded proteins. In this regard, Churchman and colleagues showed that only 65% of the germline IKZF1 variants characterized as damaging in their study were accurately classified using in silico methods [46]. To address this challenge, investigators must use alternative approaches, such as expression of variant proteins in cell lines or live animals, followed by evaluation for downstream effects. Unfortunately, these approaches can be costly as well as time and labor intensive, and they too may have limitations. This is especially apparent for hematopoietic stem cells and B cells, where mouse and human cells have unique cytokine dependencies and express different cell surface markers, suggesting that the mouse and human systems may not be entirely complementary [182]. The use of induced pluripotent stem cells (iPSCs) provides one additional approach to model inherited cancer syndromes and confirm any phenotypes arising through the use of cell lines and mouse models. Indeed, patient-derived iPSCs have already provided insights to how GATA2 deficiency affects human hematopoiesis [183].
Germ line predisposition to myeloid malignancies appearing in adulthood
Published in Expert Review of Hematology, 2018
Martina Crysandt, Kira Brings, Fabian Beier, Christian Thiede, Tim H Brümmendorf, Edgar Jost
GATA-binding protein 2 (GATA2) is a zinc finger protein acting as a transcription factor for hematopoiesis and lymphatic vessel genesis. In addition to predisposition for MDS and AML, germ line mutations in GATA2 are associated with MonoMAC and Emberger syndrome [47,48]. Patients with the same mutation can display significant interindividual variability in the clinical phenotype and the association between a specific GATA2 mutation and the individual clinical phenotype is not well understood. In patients with a MonoMAc syndrome, mutations are most often detected in the zinc finger-2 domain [49]. The development of MDS and rapid transformation in AML in families with a GATA2 mutation occurs at high penetrance and typically at young age and is often associated with acquired additional sex combs like 1 (ASXL1) mutations, monosomy 7 and a hypocellular, fibrotic bone marrow [50]. Patients with a MonoMAC syndrome suffer from severe monocytopenia, NK- and B-cell deficiency and a decrease in dendritic cells [49]. As a consequence, they often present with opportunistic viral and mycobacterial infections, pulmonary alveolar proteinosis as well as the development of MDS, chronic myelomonocytic leukemia and AML (Table 5). Myeloid disorders arise in early adulthood and the patient’s bone marrow shows a hypocellular and fibrotic aspect associated with multilineage dysplasia, monosomy 7, trisomy 8, or trisomy 1q at chromosomal analysis.