Hereditary Persistence of Fetal Hemoglobin (HPFH)

Article written and reviewed by Dr Luca Moretti

Hereditary Persistence of Fetal Hemoglobin (HPFH) is a rare genetic condition characterized by the presence of elevated levels of fetal hemoglobin (HbF) (α₂γ₂) in adulthood, generally without clinically significant hematologic abnormalities. In isolated HPFH, the complete blood count and red blood cell morphology are generally normal or nearly normal, although they may vary according to the specific variant. The condition is highly relevant to the differential diagnosis of congenital anemias and as a model for the study of innovative therapies for severe hemoglobin disorders. Recognition of HPFH is also essential because, when it coexists with other hemoglobin disorders, it can substantially modify their clinical phenotype.

Etiology, genetics and risk factors

HPFH is caused by genetic mutations that prevent physiologic postnatal silencing of the gamma-globin genes (HBG2 and HBG1) located on chromosome 11, thereby allowing persistent production of HbF after birth. At the molecular level, HPFH variants are divided into two broad categories:

• Deletional forms: large deletions of the beta-globin cluster that remove regulatory sequences responsible for silencing the gamma-globin genes. These forms are frequently identified in African and Mediterranean populations.
• Nondeletional forms: point mutations or small alterations in the promoters of the gamma-globin genes that increase gamma-chain transcription. They are often autosomal dominant and have been identified in families worldwide.

HPFH is inherited in an autosomal manner, but expression and HbF levels depend on the specific variant. In heterozygous deletional forms, HbF is often approximately 10-30%; in rare biallelic forms it may become predominant.

No environmental risk factors are known; HPFH should always be suspected when HbF remains elevated beyond infancy, particularly in the absence of microcytosis or anemia and in individuals with a family history of elevated HbF.

Fetal hemoglobin physiology and HPFH pathogenesis

Fetal hemoglobin (HbF) is the main hemoglobin during intrauterine life and in the newborn because of its high affinity for oxygen, which facilitates oxygen transfer from the mother to the fetus. The composition of HbF (α₂γ₂) distinguishes it from adult hemoglobins (HbA and HbA₂), in which gamma chains are progressively replaced by beta and delta chains during the weeks after birth under the control of complex epigenetic and transcriptional mechanisms.

In HPFH, because of the mutations, these switching mechanisms remain partially or completely ineffective: HbF synthesis continues indefinitely and may account for a substantial proportion, or even nearly all, of the adult hemoglobin. From a pathophysiologic standpoint, persistence of HbF does not cause pathologic consequences because tissue oxygen transport and release remain adequate.

Clinically, isolated HPFH is generally asymptomatic and does not cause clinically significant anemia; red blood cell morphology and hematologic parameters are usually normal or nearly normal, with variation depending on the specific variant. When it coexists with other severe hemoglobin disorders, such as beta-thalassemia or sickle cell disease, elevated HbF may attenuate the severity of the clinical phenotype.

Clinical features

HPFH is generally clinically silent. Carriers have no symptoms, signs of clinically significant anemia, or abnormalities on physical examination. The complete blood count is generally normal or nearly normal.

HPFH is almost always detected incidentally during hemoglobin screening or an evaluation for microcytic anemia, suspected thalassemia, or family testing. In the presence of other hemoglobin disorders, such as beta-thalassemia major or sickle cell disease, HPFH has a clinically favorable effect: a high, pancellular HbF fraction may attenuate hemolysis and clinical manifestations; the magnitude of the effect depends on the cellular distribution of HbF and the associated genotype.

No clinical complications attributable to isolated HPFH have been described, either in the long term or under conditions of metabolic stress.

Diagnosis and investigations

The diagnosis of HPFH is based on the integration of hemoglobin, hematologic, family and molecular findings:

• Persistently elevated HbF in adulthood, with a level that varies according to the specific variant
• Absence of clinically significant anemia, with red blood cell indices and morphology generally normal or nearly normal
• Family history of persistently elevated HbF, when present, as supportive evidence

Laboratory tests show:

• A generally normal or nearly normal complete blood count, with possible genotype-dependent variation
• Hemoglobin electrophoresis/HPLC: a variable HbF fraction; in heterozygous deletional forms it is often above 10% and in rare biallelic forms it may become predominant; HbA₂ normal or mildly reduced and HbA variable
• Red blood cell morphology without significant abnormalities

The main differential diagnosis includes delta-beta thalassemia, gamma-delta-beta thalassemia and complex deletional thalassemias, in which anemia, microcytosis and ineffective erythropoiesis may be present but are not universal.

Genetic analysis (MLPA, NGS, targeted sequencing) can identify the specific deletions or point mutations responsible for HPFH. In some cases, especially in families with other carriers, reconstruction of the inheritance pattern through segregation analysis is essential for genetic counseling and reproductive counseling.

Treatment and prognosis

There are no specific treatment indications for isolated HPFH. The condition is entirely benign, requires neither treatment nor specific monitoring, and has no adverse effect on quality of life or lifespan.

Clinical management is relevant only in individuals who also have another hemoglobin disorder, in whom HPFH must be recognized to assess prognosis and tailor the therapeutic approach. In these cases, elevated HbF may favorably modify the phenotype, but the effect depends on its proportion, pancellular or heterocellular distribution, and the genotype of the associated hemoglobin disorder.

The prognosis of isolated HPFH is excellent. When the diagnosis is made during pregnancy or genetic counseling, carriers can be reassured about the generally benign nature of isolated HPFH after diagnostic confirmation; reproductive counseling must nevertheless consider the specific variant and the partner's hemoglobin profile.

Complications

No complications are known to be associated with isolated HPFH. Clinically, the principal role of HPFH is as a phenotypic modifier in severe hemoglobin disorders: it may attenuate some manifestations of sickle cell disease or beta-thalassemia, with a magnitude that is variable and cannot be predicted from total HbF alone.

Moreover, understanding the genetic mechanisms underlying HPFH has paved the way for the development of new therapeutic strategies aimed at pharmacologically inducing HbF, an area of intensive research in hemoglobin disorders.

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