Primary polycythemias/erythrocytosis are caused by acquired or inherited mutations causing functional changes within hematopoietic stem cells or erythroid progenitors leading to an accumulation of red cells; the erythropoietin (EPO) level is decreased, and erythroid progenitors are hypersensitive or grow even independently of EPO. The most common primary erythrocytosis is polycythemia vera, an acquired clonal disorder. The other primary erythrocytosis—known as primary familial and congenital polycythemia (PFCP)—is inherited from mutations in the EPO receptor (EPOR). In contrast, secondary erythrocytoses are due to either an appropriate or inappropriate increase in the red cell mass, most often as a result of augmented levels of EPO (Prchal JT. Primary Familial and Congenital Erythrocytosis. updated 2025 Jan 23, [2016 Nov 10]. In: Adam MP, Feldman J, Mirza GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 27831681). Congenital erythrocytoses are rare, and are caused by germline mutations in various genes that are involved in the regulation of erythropoiesis. Erythropoietin (EPO) is the main physiologic hormone that regulates erythropoiesis and is important for the terminal differentiation of erythroid cells. The effects of EPO are mediated through its receptor, EPO-R, that are expressed on erythroid progenitor cells. EPO-R undergoes conformational changes after binding to EPO and induces downstream signals that promote erythropoiesis. Germline mutations EPOR are found in primary familial congenital erythrocytosis (Prchal JT. Primary Familial and Congenital Erythrocytosis. updated 2025 Jan 23, [2016 Nov 10]. In: Adam MP, Feldman J, Mirza GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 27831681). Hypoxia is one of the main stimuli for EPO production, and oxygen sensing is mainly mediated through hypoxia-inducible factors (HIFs). HIFs (HIF-1, HIF-2, and HIF-3) are heterodimeric transcription factors consisting of active alpha and the constitutively expressed beta-subunits. HIF-2 is the main regulator of EPO transcription. In the presence of oxygen, HIFs are removed rapidly through proteasomal degradation, a mechanism that involves prolyl hydroxylase in the presence of iron and Von Hippel-Lindau (VHL) protein. However, sensing of decreased oxygen, or hypoxia, prevents the HIFs from degradation, thereby increasing the HIF dimer protein levels, which then proceed to activate downstream HIF-dependent genes that promote erythropoiesis. Germline mutations in EAPS1 (encoding HIF-2a), EGLN1 (encoding PHD2), VHL genes have been described that lead to erythrocytosis. Increased hemoglobin (Hb)-oxygen affinity due to a mutant Hb can also cause erythrocytosis, as the oxygen dissociation curve is shifted to the left due to low p50. Due to the increased affinity, oxygen binds more tightly and is not readily released in the tissue, leading to tissue hypoxia. Mutations in the beta-globin gene account for the majority of the high-oxygen affinity Hb.

Congenital Erythrocytosis

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发表日期：

2026年

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Tsewang Tashi,
Josef T. Prchal

摘要

Primary polycythemias/erythrocytosis are caused by acquired or inherited mutations causing functional changes within hematopoietic stem cells or erythroid progenitors leading to an accumulation of red cells; the erythropoietin (EPO) level is decreased, and erythroid progenitors are hypersensitive or grow even independently of EPO. The most common primary erythrocytosis is polycythemia vera, an acquired clonal disorder. The other primary erythrocytosis—known as primary familial and congenital polycythemia (PFCP)—is inherited from mutations in the EPO receptor (EPOR). In contrast, secondary erythrocytoses are due to either an appropriate or inappropriate increase in the red cell mass, most often as a result of augmented levels of EPO (Prchal JT. Primary Familial and Congenital Erythrocytosis. updated 2025 Jan 23, [2016 Nov 10]. In: Adam MP, Feldman J, Mirza GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 27831681). Congenital erythrocytoses are rare, and are caused by germline mutations in various genes that are involved in the regulation of erythropoiesis. Erythropoietin (EPO) is the main physiologic hormone that regulates erythropoiesis and is important for the terminal differentiation of erythroid cells. The effects of EPO are mediated through its receptor, EPO-R, that are expressed on erythroid progenitor cells. EPO-R undergoes conformational changes after binding to EPO and induces downstream signals that promote erythropoiesis. Germline mutations EPOR are found in primary familial congenital erythrocytosis (Prchal JT. Primary Familial and Congenital Erythrocytosis. updated 2025 Jan 23, [2016 Nov 10]. In: Adam MP, Feldman J, Mirza GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 27831681). Hypoxia is one of the main stimuli for EPO production, and oxygen sensing is mainly mediated through hypoxia-inducible factors (HIFs). HIFs (HIF-1, HIF-2, and HIF-3) are heterodimeric transcription factors consisting of active alpha and the constitutively expressed beta-subunits. HIF-2 is the main regulator of EPO transcription. In the presence of oxygen, HIFs are removed rapidly through proteasomal degradation, a mechanism that involves prolyl hydroxylase in the presence of iron and Von Hippel-Lindau (VHL) protein. However, sensing of decreased oxygen, or hypoxia, prevents the HIFs from degradation, thereby increasing the HIF dimer protein levels, which then proceed to activate downstream HIF-dependent genes that promote erythropoiesis. Germline mutations in EAPS1 (encoding HIF-2a), EGLN1 (encoding PHD2), VHL genes have been described that lead to erythrocytosis. Increased hemoglobin (Hb)-oxygen affinity due to a mutant Hb can also cause erythrocytosis, as the oxygen dissociation curve is shifted to the left due to low p50. Due to the increased affinity, oxygen binds more tightly and is not readily released in the tissue, leading to tissue hypoxia. Mutations in the beta-globin gene account for the majority of the high-oxygen affinity Hb.