Hereditary persistence of fetal hemoglobin (HPFH) is a genetic condition in which the body continues to produce fetal hemoglobin into adulthood. This phenomenon deviates from the typical developmental process where fetal hemoglobin production usually ceases. Individuals with HPFH typically experience no health problems, making it a benign genetic trait.
Hemoglobin’s Role and Normal Development
Hemoglobin is a complex protein found within red blood cells. Its primary function is to transport oxygen from the lungs to body tissues and return carbon dioxide. Humans produce different types of hemoglobin throughout their lives, adapting to varying oxygen demands. These include embryonic, fetal (HbF), and adult (HbA) hemoglobin, each with a distinct molecular structure.
Fetal hemoglobin (HbF) is the main oxygen carrier during development in the womb, starting around six weeks of pregnancy. Its structure consists of two alpha globin chains and two gamma globin chains, giving it a stronger ability to bind oxygen than adult hemoglobin. This enhanced oxygen affinity allows the fetus to efficiently retrieve oxygen from the mother’s bloodstream.
The hemoglobin switch, a significant developmental shift, occurs around birth and continues into infancy. During this period, gamma globin chain production declines, and beta globin chains begin to be produced, forming adult hemoglobin (HbA). Adult hemoglobin is composed of two alpha globin chains and two beta globin chains.
By six months of age, HbA becomes the predominant hemoglobin in an infant’s blood. HbF levels, which can range from 50% to 95% at birth, typically fall to less than 5% by six months and less than 1% by two years of age. This transition optimizes the body’s oxygen transport system for life outside the womb.
The Genetic Basis of Hereditary Persistence
HPFH arises from specific genetic variations inherited from parents. These alterations disrupt normal regulatory mechanisms that typically shut down fetal hemoglobin production after birth. As a result, individuals continue to synthesize significant amounts of HbF throughout their lives.
The genetic changes for HPFH are primarily located within the beta-globin gene cluster on chromosome 11. These variations can involve large deletions or subtle point mutations in specific regions, such as the gamma gene promoter. These mutations interfere with signals that normally switch off gamma globin genes and activate beta globin genes.
Other genetic influences, such as polymorphisms in genes like BCL11A and MYB, also affect HbF levels. These genes play a role in controlling the developmental switch from fetal to adult hemoglobin. Such genetic variations lead to sustained activity of the gamma globin genes.
HPFH is often inherited in an autosomal dominant pattern; inheriting one copy of the altered gene can result in the condition. The percentage of HbF can vary considerably, typically ranging from 0.8% to 30% in those who inherit one gene copy. In rare instances, individuals inheriting two copies, or with specific combinations of other hemoglobin disorders like delta-beta thalassemia, may have HbF levels approaching 100%.
Clinical Implications and Identification
HPFH is considered a benign condition, meaning it does not typically cause health problems. Most people are asymptomatic and often discover their condition incidentally during routine blood tests or screenings for other blood disorders.
HPFH has a positive impact when it occurs alongside other inherited hemoglobin disorders, such as sickle cell disease or beta-thalassemia. In these cases, continued fetal hemoglobin can notably lessen the severity of the primary condition. This ameliorating effect occurs because HbF does not participate in the abnormal processes causing symptoms in these disorders.
For individuals with sickle cell disease, HbF inhibits the polymerization (clumping) of abnormal hemoglobin S, which causes red blood cell sickling. By preventing this, HbF helps reduce the frequency and intensity of painful crises and other complications. Similarly, in beta-thalassemia, where adult beta-globin chain production is reduced or absent, HbF can compensate for this deficiency, leading to a milder clinical presentation.
Identifying HPFH typically involves specific blood tests measuring hemoglobin types and amounts. Common diagnostic methods include hemoglobin electrophoresis and high-performance liquid chromatography (HPLC), which quantify HbF percentage in the blood. For instance, in adults, HbF levels above 1% may suggest HPFH.
Further diagnostic tools, such as flow cytometry, can assess HbF distribution within red blood cells, distinguishing between uniform (homocellular) or varied (heterocellular) presence. Genetic testing can provide a definitive diagnosis by identifying the specific mutations in the globin gene cluster responsible for the persistent fetal hemoglobin production. Since newborns naturally have high levels of HbF, testing for HPFH is more accurate when children are older.