During development, the globin genes, responsible for producing hemoglobin, are activated in a sequence. In fetal life, a specific form of hemoglobin, called the fetal hemoglobin (HbF) is produced. The fetal hemoglobin consists of two chains of alpha globin and two gamma globin chains. Around the time of birth, gamma globin production decreases significantly, while beta globin synthesis increases. Most adults have only trace amounts of HbF. Hereditary Persistence of Fetal Hemoglobin (HPFH) is a condition where significant fetal hemoglobin production continues after birth and well into adulthood. Affected subjects do not usually show hypochromia or microcytosis. The fetal hemoglobin, meanwhile, is distributed in a pancellular fashion among all the red cells. These cells resemble normal adult cells with respect to the non-hemoglobin proteins as well the oxygen dissociation curve. Individuals with HPFH are usually healthy, or present with very mild clinical conditions. Although they do not produce any delta or beta globin chains, the HbF makes up for this loss.
HPFH is caused by mutations that inhibit the synthesis of hemoglobin A and A2. Essentially, this stems from the absence of production of the beta and delta globin chains. HbF is produced as a compensatory mechanism for the loss of HbA. Various studies have identified several mutations causing HPFH. These include both deletional and non-deletional types of mutations. Most of the deletions have been found in the gamma-delta intergenic region, and are hypothesized to deregulate the normal developmental pattern of gamma-globin gene expression by juxtaposing normally distant cis-acting factors into the vicinity of the gamma genes. The deletional types of mutations are mostly point mutations that have been seen to occur in the promoter region of either of the two highly similar gamma-globin genes; HBG1 and HBG2.