Blood defects Deletion of both<unk>  genes in mice is lethal by day 10 of embryogenesis due to a total failure in the formation of mature blood cells. Inactivation of one mouse<unk>  gene is neither lethal nor associated with most of the signs of human<unk> ; however, these animals do show a ~50% reduction in their hematopoietic stem cells along with a reduced ability to repopulate the bone marrow of mouse recipients. The latter findings, human clinical studies, and experiments on human tissues support the conclusion that in humans both parental<unk>  genes are required for sufficient numbers of hematopoietic stem cells to emerge from the hemogenic endothelium during embryogenesis and for these cells and subsequent progenitor cells to survive, self-renew, and differentiate into mature cells. As<unk>  deficient individuals age, their deficiency in hematopoietic stem cells worsens, probably as a result of factors such as infections or other stresses. In consequence, the signs and symptoms of their disease appear and/or become progressively more severe. MonoMAC-afflicted individuals exhibit reduced levels of common lymphoid progenitor cells (i.e. a heterogenous group of precursors to various lymphocyte types) and granulocyte-macrophage progenitor cells (i.e. precursors to granulocytes and monocytes). In mice and presumably humans,<unk>  also leads to reduced levels of early erythrocyte stem cells. While our understanding of human hematopoiesis is incomplete, it is proposed that these or related progenitor cell reductions causes a progressively worsening depletion of circulating and/or tissue bound B cells, NK cells, T helper cells, monocytes, plasmacytoid dendritic cells, neutrophils, and/or red blood cells. In consequence,<unk>  deficient individuals may exhibit the clinically significant disorders of chronic neutropenia, aplastic anemia, bone marrow failure, or the myelodysplastic syndrome. However, the role of<unk>  in leading to a leukemias is not understood, particularly since mutations which increase the activity of this transcription factor appear to be associated with the progression of non-familial AML as well as development of the blast crisis in chronic myelogenous leukemia. Immunologic defects === The depletion of hematologic cells, particularly dendritic cells, caused by<unk>  (see previous section) also appears responsible for the development of defective innate and adaptive immune responses. In consequence, these individuals become increasing susceptibility to infectious agents and to cancers caused by infective agents. This defect in mounting immune responses is mostly restricted to new antigenic challenges. That is, secondary immune responses to which individuals had mounted effective primary immune responses before<unk>  paralyzed their immune system generally remain intact. Immune system deterioration would also appear responsible for the development of the pathological autoimmune reactions which afflicted individuals may mount against their own tissues. Lymphedema The<unk>  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<unk>  causes a failure to develop competent valves and/or vessels in the lymphatic system and thereby leads to lymphedema. Hearing loss<unk> -induced abnormalities in the lymphatic system are also proposed to be responsible for a failure in generating the perilymphatic space around the inner ear's semicircular canals, which in turn underlies the development of sensorineural hearing loss in<unk>  deficient individuals, particularly those diagnosed with the Emberger syndrome. Other defects The pathophysiology behind the other defects associated with<unk>  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<unk>  but not a direct result of low cellular levels of the<unk>  transcription factor.
GATA2 deficiency
WNT4 deficiency
Janus kinase 3 deficiency
ZC4H2 deficiency
CDK13-related disorder
LRBA deficiency
ZAP70 deficiency
1p36 deletion syndrome