HPFH

Hereditary persistence of fetal hemoglobin (HPFH) is a genetic condition in which fetal hemoglobin (HbF) remains expressed in adult erythroid cells. Most individuals with HPFH are asymptomatic, and the condition is often discovered incidentally when HbF levels are measured for other reasons or when evaluating coexisting hemoglobin disorders such as sickle cell disease or beta-thalassemia.

HPFH is categorized into deletional and non-deletional forms. Deletional HPFH results from large deletions in the beta-globin gene cluster on chromosome 11 that remove delta and beta globin genes and associated regulatory sequences, causing upregulation of gamma-globin expression. Non-deletional HPFH arises from point mutations in the promoters of gamma-globin genes (HBG1 and HBG2) or in other regulatory elements, leading to persistent HbF production without large chromosomal deletions. Inheritance is typically autosomal dominant for most forms, with variable penetrance.

Pathophysiology involves altered regulation of the gamma-globin genes, so HbF production continues into adulthood. HbF can comprise a substantial portion of total hemoglobin, with levels often ranging from 20% to very high values in some individuals. The presence of HbF can mitigate the clinical severity of coexisting beta-hemoglobinopathies, such as reducing hemolysis or vaso-occlusive complications in sickle cell disease.

Diagnosis relies on finding elevated HbF by hemoglobin analyses, such as high-performance liquid chromatography or electrophoresis, followed by genetic testing to identify HPFH-associated deletions or gamma-globin regulatory mutations. HPFH must be differentiated from other causes of elevated HbF, including beta-thalassemia and sickle cell disease with concomitant HbF elevation.

There is no specific treatment for HPFH itself; management focuses on coexisting conditions. Genetic counseling may be offered, given the autosomal dominant inheritance pattern.