Congenital erythrocytosis.

Area of Science:

• Hematology
• Genetics
• Molecular Biology

Background:

• Erythrocytosis, or increased red cell mass, is classified as primary or secondary based on the defect's origin.
• Inherited/congenital erythrocytosis (CE) is increasingly identified after excluding acquired causes.
• Molecular mechanisms of CE have been elucidated over the past two decades.

Purpose of the Study:

• To review the current spectrum of mutations causing congenital erythrocytosis.
• To examine the distinct pathogenetic mechanisms underlying CE.
• To highlight the growing recognition of CE globally.

Main Methods:

• Literature review of genetic mutations associated with congenital erythrocytosis.
• Analysis of molecular pathways involved in erythropoietin (EPO) regulation and oxygen sensing.
• Examination of identified mutations in genes such as EPOR, VHL, PHD2, EPAS1, globin, and BPGM.

Main Results:

• Gain-in-function mutations in the erythropoietin receptor gene cause primary familial and congenital polycythemia.
• Loss-of-function mutations in VHL and PHD2/EGLN1, and gain-of-function mutations in HIF-2α (EPAS1), lead to constitutive EPO signaling.
• Mutations in globin genes and bisphosphoglycerate mutase (BPGM) can alter hemoglobin oxygen affinity, causing CE.

Conclusions:

• CE arises from diverse genetic defects impacting EPO signaling and oxygen transport.
• Understanding these genetic underpinnings is vital for accurate diagnosis and potential therapeutic strategies.
• The global prevalence and recognition of CE are increasing, necessitating continued research into its molecular basis.