Delta-beta thalassemia (δβ-thalassemia)

Article written and reviewed by Dr Luca Moretti

Delta-beta thalassemia is a rare form of thalassemia characterized by reduced or absent simultaneous synthesis of the delta (δ) and beta (β) globin chains, with the beta chain required for HbA and the delta chain limited to the small HbA2 fraction. Although less common than alpha and beta forms, this condition is of considerable clinical and genetic interest because of the diversity of molecular patterns, clinical variability, and its implications for the differential diagnosis of microcytic anemias, reproductive counseling, and newborn screening.

From a pathophysiologic standpoint, the combined loss of synthesis of both chains creates an imbalance in hemoglobin production, with persistent expression of fetal hemoglobin (HbF) into adulthood and reduced formation of HbA and HbA2. This distinctive setting may range from asymptomatic forms to thalassemia intermedia, often with chronic anemia of variable severity and associated systemic manifestations.

Etiology and Genetics

Delta-beta thalassemia is caused mainly by large deletions of the beta-globin cluster on chromosome 11 involving both the HBD (delta) and HBB (beta) genes. These deletions vary in size and location: the most common forms completely remove both genes and may involve adjacent regulatory regions; when the deletion also includes the gamma genes, the disorder instead falls within the complex gamma-delta-beta thalassemias. More rarely, nondeletional delta-beta thalassemia phenotypes related to regulatory variants of the beta-globin cluster have been described; their mechanism and classification depend on the specific variant and are not equivalent to all conditions with persistent HbF.

The genetic abnormalities can be summarized as follows:

• Large deletions that remove the HBD and HBB genes and sometimes adjacent regulatory sequences; involvement of the gamma genes instead points toward gamma-delta-beta thalassemia.
• Rare nondeletional regulatory variants of the beta-globin cluster with a delta-beta thalassemia phenotype, to be characterized molecularly on a case-by-case basis.
• Compound forms in which the delta-beta deletion is associated with additional defects (alpha-thalassemia, HPFH, other globin variants).

Inheritance is autosomal. Heterozygous individuals generally have microcytosis with increased HbF and may be asymptomatic; biallelic forms or combinations with other beta-globin variants may produce a thalassemia intermedia phenotype.

Loss of delta and beta chain synthesis on the affected allele reduces overall production of HbA and HbA2; in heterozygotes, however, the normal allele continues to produce both fractions, while HbF increases compensatorily. The degree of compensation provided by HbF is highly variable and depends on the nature of the mutation and any modifying genetic determinants, including variants associated with HPFH (Hereditary Persistence of Fetal Hemoglobin).

It is essential to distinguish delta-beta thalassemia from HPFH: in HPFH there is no significant anemia or ineffective erythropoiesis, whereas delta-beta thalassemia may have a more complex clinical picture with chronic anemia, microcytosis and, in some cases, erythroid marrow expansion.

Pathogenesis and Pathophysiology

The pathophysiology of delta-beta thalassemia depends on reduced synthesis of beta and delta chains from the affected allele, with a compensatory increase in gamma-chain synthesis and therefore HbF. In heterozygotes, the normal allele continues to produce HbA. In healthy individuals, the transition from fetal to adult hemoglobin occurs during the first months of life through activation of the beta and delta genes, which progressively replace gamma-chain production. Persistent HbF partly compensates for beta-chain deficiency and tends to attenuate globin-chain imbalance; it is not itself the primary mechanism of symptoms.

Accumulation of unpaired alpha chains due to deficiency of non-alpha chains causes oxidative injury and ineffective erythropoiesis, with premature death of erythroid precursors and a risk of chronic anemia. However, the presence of HbF attenuates the severity of manifestations compared with beta-thalassemia major. In more severe forms, chronic stimulation of erythropoiesis produces erythroid marrow hyperplasia, splenomegaly and extramedullary hematopoiesis.

The risk of tissue hypoxia increases under conditions of greater oxygen demand, such as acute infections, rapid growth, pregnancy or cardiopulmonary comorbidities. Clinical severity is strongly modulated by the residual proportion of HbF, the genetic background and possible interactions with other hemoglobinopathies.

Clinical Features

The clinical presentation of delta-beta thalassemia is extremely heterogeneous. Simple carriers are generally asymptomatic or have only mild hypochromic microcytic anemia, often unrecognized or mistaken for other causes of microcytosis.

In homozygous individuals or compound heterozygotes with other thalassemic forms, the clinical picture may resemble thalassemia intermedia: moderate chronic anemia, persistent pallor, fatigue, reduced exercise tolerance, splenomegaly and, in more severe cases, signs of erythroid expansion such as bone hypertrophy and thalassemic facies. During infections or other periods of erythropoietic stress, anemia, jaundice and reticulocytosis may worsen.

Elevated HbF is not uncommonly detected in apparently healthy individuals during family screening, prenatal investigations or routine testing in pregnancy. In rare biallelic forms, the diagnosis may be suspected because of anemia and persistently very high HbF beyond the first months of life.

In more marked forms, symptoms may worsen during growth, pregnancy or infections because of increased erythropoietic demand; in rare cases, an occasional transfusion may be required.

Diagnosis and Investigations

The diagnosis of delta-beta thalassemia is established through a stepwise evaluation that begins with clinical observation and routine laboratory tests and proceeds, only after suspicion arises, to specific second- and third-level investigations. The condition is often first suspected when an otherwise unexplained hypochromic microcytic anemia is found, with a normal or increased red blood cell count. In heterozygous individuals, the abnormalities may be extremely subtle, whereas in homozygous or compound heterozygous cases suspicion may arise from chronic anemia, marked microcytosis, splenomegaly and, occasionally, associated systemic manifestations.

The complete blood count typically documents microcytic anemia (reduced mean corpuscular volume - MCV), with variably reduced hemoglobin, decreased MCH and often a normal or mildly increased red blood cell count.
The peripheral blood smear shows, depending on severity:

• marked microcytosis and hypochromia
• poikilocytosis, target cells
• sometimes mild reticulocytosis

Given these findings, the most common causes of microcytic anemia must first be excluded, including iron deficiency, other thalassemias (especially alpha and beta), structural hemoglobinopathies and chronic inflammatory conditions. Measurement of ferritin and other iron parameters helps distinguish thalassemia from iron deficiency, but the two conditions may coexist and results must be interpreted in the clinical context and together with hemoglobin studies.

Only when microcytosis cannot be explained by common causes, and particularly when HbF is persistently elevated on electrophoresis or HPLC, are second-level tests pursued. In heterozygous individuals, electrophoresis or HPLC shows HbA present, HbA2 low or at the lower limit of normal and HbF increased, often approximately 5-20%; in rare biallelic forms HbA may be markedly reduced or absent and HbF may become predominant.

At this point, the diagnostic pathway proceeds to second-level investigations: the distinction between delta-beta thalassemia and HPFH may be supported by the hematologic phenotype, the cellular distribution of HbF and globin-synthesis studies, whereas DNA analysis enables molecular definition of the specific abnormality. The main techniques include:

• MLPA (Multiplex Ligation-dependent Probe Amplification) and PCR to detect deletions involving the HBD and HBB genes
• NGS (Next Generation Sequencing) to identify point mutations or complex abnormalities
• Extended family analysis to characterize the inheritance pattern correctly

The differential diagnosis, which may be particularly challenging, must include HPFH (in which anemia and ineffective erythropoiesis are absent), beta-thalassemia major, rare variants such as gamma-delta-beta thalassemia and mixed combinations of thalassemia. A multidisciplinary approach involving referral centers for hemoglobinopathies is often necessary for accurate classification and genetic counseling of family members.

Treatment and Prognosis

Clinical management depends on disease severity. Heterozygous carriers require no specific treatment, but they should be identified to prevent inappropriate therapy and to provide accurate genetic counseling. In intermediate cases, periodic follow-up with hematologic monitoring, folic acid supplementation and transfusions only in selected situations of severe symptomatic anemia is indicated.

In forms with an intermediate or non-transfusion-dependent phenotype, iron overload must be monitored even in the absence of regular transfusions, because ineffective erythropoiesis may reduce hepcidin and increase intestinal iron absorption.

In transfusion-dependent cases, iron overload must be controlled, with iron chelation therapy introduced when indicated. Splenectomy is rarely necessary and is reserved for severe hypersplenism with clinically relevant cytopenias or symptomatic splenomegaly.

The prognosis is generally favorable, especially in forms with a substantial residual proportion of HbF: most patients maintain a satisfactory quality of life and a lower risk of complications than classic beta-thalassemia major.

Complications

The main complications, typically confined to the most severe cases, include:

• Iron overload due to increased intestinal absorption and/or repeated transfusions.
• Gallstones due to increased red blood cell turnover.
• Splenomegaly and hypersplenism with a risk of cytopenias.
• Extramedullary hematopoiesis (paraspinal masses, bone expansion).
• Pregnancy: possible worsening of anemia, requiring specialist monitoring and, in some cases, transfusions.

Early recognition and multidisciplinary management minimize the risk of serious events and optimize quality of life.

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