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Beta-Thalassemia

Synonyms: Cooley's Anemia, Mediterranean Anemia
, MD
Dipartimento di Scienze Mediche e Sanità Pubblica
Università degli Studi di Cagliari
Ospedale Pediatrico Microcitemico Antonio Cao
Cagliari, Italy

Initial Posting: ; Last Update: January 25, 2018.

Summary

Clinical characteristics.

Beta-thalassemia (β-thalassemia) is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis.

Individuals with thalassemia major have severe anemia and hepatosplenomegaly; they usually come to medical attention within the first two years of life. Without treatment, affected children have severe failure to thrive and shortened life expectancy. Treatment with a regular transfusion program and chelation therapy, aimed at reducing transfusion iron overload, allows for normal growth and development and may improve the overall prognosis.

Individuals with thalassemia intermedia present later and have milder anemia that does not require regular treatment with blood transfusion. These individuals are at risk for iron overload secondary to increased intestinal absorption of iron as a result of ineffective erythropoiesis.

Diagnosis/testing.

The diagnosis of β-thalassemia relies on measuring red blood cell indices that reveal microcytic hypochromic anemia, nucleated red blood cells on peripheral blood smear, hemoglobin analysis that reveals decreased amounts of HbA and increased amounts of hemoglobin F (HbF) after age 12 months, and the clinical severity of anemia. Identification of biallelic pathogenic variants in HBB (the gene encoding the hemoglobin subunit beta) on molecular genetic testing may be useful for diagnosis in at-risk individuals under age 12 months who have a positive or suggestive newborn screening result and/or unexplained microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear.

Management.

Treatment of manifestations:

  • Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron. Bone marrow transplantation (BMT) from an HLA-identical sib represents an alternative to traditional transfusion and chelation therapy. Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk for graft-vs-host disease.
  • Thalassemia intermedia. Symptomatic therapy based on splenectomy in most affected individuals, sporadic red cell transfusions in some, folic acid supplementation, and iron chelation.

Prevention of secondary complications: Assessment of iron overload through one or more of the following: serum ferritin concentration, liver biopsy, magnetic biosusceptometry, and MRI techniques; prevention of transfusional iron overload with adequate iron chelation therapy (i.e., desferroxamine B, deferiprone, deferasirox); assessment of myocardial siderosis by MRI and monitoring of cardiac function; treatment of osteoporosis, including consideration of bisphosphonate therapy.

Surveillance: Thalassemia major: monitoring of the effectiveness/side effects of transfusion therapy and chelation therapy in affected individuals of all ages by monthly physical examination; trimonthly assessment of liver function tests, determination of serum ferritin concentration, and evaluation of growth and development (during childhood); annual evaluation of eyes, hearing, heart, endocrine function (thyroid, endocrine pancreas, parathyroid, adrenal, pituitary), liver (ultrasound examination), and myocardial and liver MRI. In adults: bone densitometry to assess for osteoporosis; serum alpha-fetoprotein concentration for early detection of hepatocarcinoma in those with hepatitis C and iron overload; regular gallbladder echography for early detection of cholelithiasis for those at risk.

Agents/circumstances to avoid: Alcohol consumption, iron-containing preparations.

Evaluation of relatives at risk: If the pathogenic variants have been identified in an affected family member, molecular genetic testing of at-risk sibs should be offered to allow for early diagnosis and appropriate treatment. Hematologic testing can be used if the pathogenic variants in the family are not known.

Pregnancy management: Women with thalassemia intermedia who have never received a blood transfusion or who received a minimal quantity of blood are at risk for severe alloimmune anemia if blood transfusions are required during pregnancy.

Genetic counseling.

The β-thalassemias are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (i.e., carriers) may be slightly anemic but are clinically asymptomatic. Carriers are often referred to as having thalassemia minor (or β-thalassemia minor). Carrier testing for individuals at risk (including family members, gamete donors, and members of at-risk ethnic groups) is possible. Once both HBB pathogenic variants have been identified in a couple at risk, prenatal testing and preimplantation genetic diagnosis are possible.

GeneReview Scope

Beta-Thalassemia: Included Phenotypes
  • Thalassemia major
  • Thalassemia intermedia
  • Thalassemia minor

Diagnosis

Suggestive Findings

Beta-thalassemia (β-thalassemia) major should be suspected in an infant or child younger than age two years with the following clinical or newborn screening findings:

  • Clinical findings
    • Severe microcytic anemia
    • Mild jaundice
    • Hepatosplenomegaly
    Note: If untreated, affected children usually manifest failure to thrive and expansion of the bone marrow to compensate for ineffective erythropoiesis.
  • Newborn screening findings. A positive or suggestive screen done through newborn screening (i.e., through capillary electrophoresis, isoelectric focusing, or high-performance liquid chromatography on newborn blood spots)

Thalassemia intermedia should be suspected in individuals who present at a later age with similar but milder clinical findings. Individuals with thalassemia intermedia do not require regular treatment with blood transfusion.

Thalassemia minor is usually clinically asymptomatic, but sometimes a mild anemia is present.

Establishing the Diagnosis

The diagnosis of β-thalassemia is established in a proband older than age 12 months based on the hematologic findings of microcytic hypochromic anemia (Table 1), anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and hemoglobin analysis that reveals decreased amounts or complete absence of hemoglobin A and increased amounts of hemoglobin F (Table 2).

The diagnosis of β-thalassemia is established in a proband younger than age 12 months based on the following findings:

  • Positive or suggestive newborn screening result
    • The diagnosis of β0-thalassemia (in which no beta-globin protein is produced) can be made at birth by detecting a complete absence of hemoglobin A.
    • Definitive diagnosis of β+-thalassemia (in which beta-globin protein is produced but at a reduced level) by these techniques is not possible in the newborn period because the diminished amount of hemoglobin A overlaps the range for normal babies.
  • Microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear
  • Biallelic pathogenic variants in HBB identified on molecular genetic testing (see Table 3)

Hematologic Findings

Red blood cell indices show microcytic anemia (Table 1).

Table 1.

Red Blood Cell Indices in Beta-Thalassemia

Red Blood Cell IndexNormal 1AffectedCarrier 1
MaleFemaleβ-Thal Majorβ-Thal Minor
Mean corpuscular volume (MCV fl)89.1±5.0187.6±5.550-70<79
Mean corpuscular hemoglobin (MCH pg)30.9±1.930.2±2.112-20<27
Hemoglobin (Hb g/dL)15.9±1.014.0±0.9<7Males: 11.5-15.3
Females: 9.1-14

Peripheral blood smear

  • Affected individuals demonstrate the red blood cell (RBC) morphologic changes of microcytosis, hypochromia, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells), and nucleated red blood cells (i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is markedly increased following splenectomy.
  • Carriers demonstrate reduced mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) (Table 1), and RBC morphologic changes that are less severe than in affected individuals. Erythroblasts are normally not seen.

Qualitative and quantitative hemoglobin analysis (by cellulose acetate electrophoresis and DE-52 microchromatography or HPLC) identifies the amount and type of hemoglobin present. The following hemoglobin (Hb) types are most relevant to β-thalassemia:

  • Hemoglobin A (HbA): two globin alpha chains and two globin beta chains (α2β2)
  • Hemoglobin F (HbF): two globin alpha chains and two globin gamma chains (α2γ2)
  • Hemoglobin A2 (HbA2): two globin alpha chains and two globin delta chains (α2δ2)

The hemoglobin pattern in β-thalassemia varies by β-thalassemia type (Table 2).

Table 2.

Hemoglobin Patterns in Beta-Thalassemia (Age >12 Months)

Hemoglobin TypeNormal 1AffectedCarrier
βº-Thal Homozygotes 2β+-Thal Homozygotes or β+/βº Compound Heterozygotes 3β-Thal Minor
HbA96%-98%010%-30%92%-95%
HbF<1%95%-98%70%-90%0.5%-4%
HbA22%-3%2%-5%2%-5%>3.5%
1.
2.

βº-thalassemia: complete absence of globin beta chain production

3.

β+-thalassemia: variable degree of reduction of globin beta chain synthesis

Hemoglobin electrophoresis and HPLC also detect other hemoglobinopathies (S, C, E, OArab, Lepore) that may interact with β-thalassemia.

Click here (pdf) for information on the results of in vitro synthesis of radioactive labeled globin chains in affected individuals.

Molecular Genetic Testing

The recommended molecular genetic testing approach for beta-thalassemia is single-gene testing:

Table 3.

Molecular Genetic Testing Used in Beta-Thalassemia

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
HBBSequence analysis 3Almost 100%
Gene-targeted deletion/duplication analysis 4Rare 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

Clinical Characteristics

Clinical Description

Beta-thalassemia (β-thalassemia) is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis.

The phenotypes of the homozygous β-thalassemias include thalassemia major and thalassemia intermedia. The clinical severity of the β-thalassemia syndromes depends on the extent of alpha globin chain / non-alpha globin chain (i.e., β+ γ) imbalance. The non-assembled alpha globin chains that result from unbalanced alpha globin chain / non-alpha globin chain synthesis precipitate in the form of inclusions. These alpha globin chain inclusions damage the erythroid precursors in the bone marrow and in the spleen, causing ineffective erythropoiesis. The bone marrow is extremely cellular, mainly as a result of marked erythroid hyperplasia, with a myeloid/erythroid ratio reversed from the normal (3 or 4) to 0.1 or less. However, bone marrow examination is usually not necessary for diagnosis of affected individuals.

Individuals with thalassemia major usually come to medical attention within the first two years of life; they subsequently require regular red blood cell transfusions to survive. Those who present later and do not regularly require transfusion are said to have thalassemia intermedia.

β-Thalassemia Major

Presentation. Clinical presentation of thalassemia major occurs between ages six and 24 months.

  • Affected infants fail to thrive and become progressively paler.
  • Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly may occur.
  • If the diagnosis of thalassemia major is established at this stage and if a regular transfusion program that maintains a minimum Hb concentration of 95 to 105 g/L is initiated, growth and development are normal at least until age ten to 11 years.

Complications. After age ten to 11 years, affected individuals are at risk of developing severe complications related to iron overload, depending on their compliance with chelation therapy (see Management). In individuals who have been regularly transfused, iron overload results mainly from transfusions.

Complications of iron overload include the following:

  • In children, growth restriction and failure of sexual maturation
  • In adults, involvement of the heart (dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrine glands (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands)

Other complications:

  • Hypersplenism
  • Chronic hepatitis (resulting from infection with the viruses that cause hepatitis B and/or hepatitis C)
  • Cirrhosis (from iron overload and chronic hepatitis)
  • HIV infection
  • Venous thrombosis
  • Osteoporosis

The risk for hepatocellular carcinoma is increased secondary to liver viral infection, iron overload, and longer survival [Borgna-Pignatti et al 2014, Moukhadder et al 2017].

Prognosis. The prognosis for individuals with β-thalassemia major has dramatically improved over the last decades with the advent of noninvasive methods to measure organ iron before the appearance of clinical symptoms, new chelators, and increased blood safety measures.

After 2000, all of these developments have led to a significant trend in decreasing cardiac mortality, previously reported to cause 71% of the deaths in individuals with β-thalassemia major [Borgna-Pignatti et al 2004, Telfer et al 2006, Modell et al 2008]. Recent studies show that despite geographic differences, most individuals with transfusion-dependent thalassemia have normal cardiac iron, but a significant proportion have simultaneous liver iron overload [Aydinok et al 2015b].

Without treatment. The classic clinical picture of thalassemia major is presently only seen in some developing countries, in which the resources for carrying out long-term transfusion programs are not available. The most relevant features of untreated or poorly transfused individuals:

  • Growth restriction
  • Pallor
  • Jaundice
  • Brown pigmentation of the skin
  • Poor musculature
  • Genu valgum
  • Hepatosplenomegaly
  • Leg ulcers
  • Development of masses from extramedullary hematopoiesis
  • Skeletal changes that result from expansion of the bone marrow, including:
    • Deformities of the long bones of the legs
    • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth)
    • Osteoporosis

Individuals who have not been regularly transfused usually die in the first two decades. Individuals who have been poorly transfused are also at risk for complications of iron overload.

β-Thalassemia Intermedia

Clinical features are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from iron accumulation and hypercoagulable state secondary to the lipid membrane composition of the abnormal red blood cells [Cappellini et al 2012].

  • By definition, transfusions are not required, or only occasionally required.
  • Iron overload occurs mainly from increased intestinal absorption of iron caused by deficiency of hepcidin, a 25-amino acid peptide produced by hepatocytes that plays a central role in the regulation of iron homeostasis [Nemeth & Ganz 2006, Origa et al 2007]. Hepcidin deficiency is associated with ineffective erythropoiesis. The associated complications of iron overload present later, but may be as severe as those seen in individuals with thalassemia major who depend on transfusions.

Genotype-Phenotype Correlations

βº variants and some β+ variants are associated with a severe phenotype and result in thalassemia major in the homozygous or compound heterozygous state; however, clinical severity may be modified to thalassemia intermedia if ameliorating genetic factors are present.

Some β+ variants have a mild phenotype; however, the clinical severity in the homozygous state or compound heterozygous state with other β0 or β+ variants is variable.

A few β+ silent variants (with a normal or borderline HbA2 and a normal MCH in the heterozygous state) result in very mild clinical severity in the homozygous state or compound heterozygous state with severe β0 or + variants.

Common mild and silent pathogenic variants are listed in Table 5.

Clinical presentation of compound heterozygosity for β-thalassemia and HbE ranges from severe to asymptomatic.

Ameliorating Genetic Factors

Clinical severity of β+- or βº-thalassemia may be ameliorated by coinheritance of pathogenic variants in HBA1 or HBA2, associated with α-thalassemia, which reduce alpha globin expression, thereby decreasing the alpha/non-alpha globin chain imbalance. Due to clinical variability, HBA1 and HBA2 genotypes cannot be used to predict clinical outcome.

The coinheritance of some genetic determinants able to sustain a continuous production of gamma globin chains (HbF) in adult life may also reduce the extent of alpha/non-alpha globin chain imbalance:

  • The β-thalassemia pathogenic variants that increase gamma globin chain (HbF) output:
    • δβº-thalassemia caused by deletions of variable size in the HBB gene cluster
    • Deletions that remove only the 5' region of the HBB promoter, which also results in high levels of HbA2
  • Co-transmission of hereditary persistence of fetal hemoglobin (HPFH), which is the result of single-nucleotide variants in the hemoglobin Gγ (HBG2) or hemoglobin Aγ (HBG1) promoter (most commonly c.-158C>T in HBG2 and c.-117G>A in HBG1; see Table 4 and Table 5), may result in a milder phenotype.
  • The c.-196C>T HBG1 variant in cis with p.Gln40Ter has been found on some Sardinian β-thalassemia chromosomes (Sardinian δβº-thalassemia).

Other genetic loci that are not linked to the HBB gene cluster and may have an ameliorating effect on clinical features of β-thalassemia have been suggested [Sankaran et al 2008, Uda et al 2008, Galanello et al 2009, Thein et al 2009, Borg et al 2010, Satta et al 2011, Gallienne et al 2012].

In some instances, heterozygous β-thalassemia may lead to the phenotype of thalassemia intermedia instead of the asymptomatic carrier state. Known molecular mechanisms include the following:

  • Heterozygosity for pathogenic variants in HBB that result in hyper-unstable hemoglobins (dominant β-thalassemia), which precipitate in the red cell membrane together with unassembled alpha globin chains, resulting in markedly ineffective erythropoiesis. Most of these HBB pathogenic variants lie in the third exon and lead to the production of a markedly unstable Hb variant often not detectable in peripheral blood.
  • Double heterozygosity for typical β-thalassemia pathogenic variants and the triple or (less frequently) quadruple alpha gene arrangement (ααα/αα or ααα/ααα or αααα/αα) may increase the imbalance in the ratio of alpha/non-alpha globin chains. Duplications of the entire alpha globin gene cluster have been reported to cause thalassemia intermedia in association with the β-thalassemia carrier state [Harteveld et al 2008, Sollaino et al 2009, Origa et al 2014].

Genetic determinants capable of sustaining continuous production of HbF in adult life outside the HBB gene cluster have been mapped to chromosome 2p16 and chromosome 6q23 [Uda et al 2008].

  • The 2p16 locus identified by GWAS mapped to BCL11A (rs11886868; c.386-24278C>T in intron 2) and was found strongly associated with HbF levels. The c.386-24278C allele was significantly more common in 0 homozygotes for p.Gln40Ter with a mild phenotype and in patients with mild sickle cell disease [Lettre et al 2008, Uda et al 2008]. The c.386-24278C>T genotype in young patients with homozygous β-thalassemia and sickle cell anemia may serve as a prognostic indication for the severity of the disease. Furthermore, targeted downregulation of BCL11A in patients could elevate HbF levels and thereby ameliorate the severity of these inherited anemias.
  • A genetic variant associated with HbF variation was mapped to the HBS1L-MYB region on chromosome 6 [Creary et al 2009]. Recent studies have shown that the HBS1L-MYB intergenic variants contain regulatory sequences controlling MYB expression. Coinheritance of these HPFH determinants and alpha-thalassemia contribute in the amelioration of the phenotype of homozygous β-thalassemia accounting for 75% of difference in clinical severity [Galanello et al 2009].

Recently, it was suggested that three factors – the type of pathogenic variant in HBB, HBA gene defects, and fetal hemoglobin production modulators (HBG2:c.-158C>T, HBS1L-MYB intergenic region, and the BCL11A: c.386-24278G>A) – combine to build a predictive score of disease severity, based on a representative cohort of 890 patients with non-transfusion-dependent and transfusion-dependent β-thalassemia. The effect of these loci on the transfusion-free survival probability and on the age at which the patient started regular transfusions was demonstrated [Danjou et al 2015].

Other modifying factors. The clinical phenotype of homozygous β-thalassemia may also be modified by the coinheritance of secondary genetic factors mapping outside the β-globin gene cluster, which influence the complications of the thalassemia phenotype [Origa et al 2008, Origa et al 2009].

Nomenclature

β-thalassemia includes three main forms:

  • β-thalassemia major, also referred as "Cooley’s anemia," "Mediterranean anemia," or "transfusion-dependent thalassemia (TDT);
  • β-thalassemia intermedia; and
  • Thalassemia minor, called "β-thalassemia carrier," "β-thalassemia trait," or "heterozygous β-thalassemia."

Non-transfusion-dependent thalassemias (NTDT) is a term used to label patients who do not require lifelong regular transfusions for survival; NTDT encompasses β-thalassemia intermedia, hemoglobin E/β-thalassemia (mild and moderate forms), and α-thalassemia intermedia (hemoglobin H disease).

Prevalence

β-thalassemia is prevalent in populations in the Mediterranean, the Middle East, the Transcaucasus, Central Asia, the Indian subcontinent, and the Far East. It is also common in populations of African heritage. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia.

The high gene frequency of β-thalassemias in these regions is most likely related to selective pressure from malaria. This distribution is quite similar to that of endemic Plasmodium falciparum malaria. However, because of population migration and (to a limited degree) the slave trade, β-thalassemia is now also common in northern Europe, North and South America, the Caribbean, and Australia.

Differential Diagnosis

β-thalassemia associated with other features. In rare instances the β-thalassemia defect does not lie in HBB or in the β-globin gene cluster. In instances in which the β-thalassemia trait is associated with other features, the molecular lesion has been found either in the gene encoding the transcription factor TFIIH (β-thalassemia trait associated with xeroderma pigmentosum and trichothiodystrophy) or in the X-linked transcription factor GATA-1 (X-linked thrombocytopenia with thalassemia) (see GATA1-Related X-Linked Cytopenia) [Viprakasit et al 2001, Freson et al 2002].

Few conditions share similarities with homozygous β-thalassemia.

  • The genetically determined sideroblastic anemias are easily differentiated because of ring sideroblasts in the bone marrow and variably elevated serum concentration of erythrocyte protoporphyrin. Most sideroblastic anemia is associated with defects in the heme biosynthetic pathway, especially δ-aminolevulinic acid synthase (see also X-Linked Sideroblastic Anemia and Ataxia).
  • Congenital dyserythropoietic anemias do not have high HbF and do have other distinctive features, such as multinuclearity of the red blood cell precursors (see Congenital Dyserythropoietic Anemia Type I).
  • A few acquired conditions associated with high HbF (juvenile chronic myeloid leukemia, aplastic anemia) may be mistaken for β-thalassemia, even though they have very characteristic hematologic features.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with β-thalassemia, the following evaluations are recommended if they have not already been completed:

  • The initial step following diagnosis of β-thalassemia in an individual is to distinguish between those who have thalassemia intermedia (requiring intermittent transfusions on an as-needed basis) from those with thalassemia major (who need a regular transfusion program). See Establishing the Diagnosis.
    The following should be included in the investigations when deciding whom to transfuse:
    • Confirmed diagnosis of thalassemia; and
    • Hemoglobin level <7 g/dL on two occasions, more than two weeks apart (excluding all other contributory causes, such as infections), or presence of the following features, regardless of hemoglobin level:
      • Facial changes
      • Poor growth
      • Bony fractures
      • Clinically significant extramedullary hematopoiesis
  • Consultation with a clinical geneticist and/or genetic counselor is appropriate.

Treatment of Manifestations

Comprehensive reviews of the management of thalassemia major and thalassemia intermedia have been published by the Thalassemia International Federation [Taher et al 2013, Cappellini et al 2014] and are available at the TIF website.

Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron.

  • Before starting the transfusions, the following are absolutely necessary:
    • Hepatitis B vaccination
    • Extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy and serum immunoglobulin determination – the latter of which detects individuals with IgA deficiency, who need special (repeatedly washed) blood unit preparation before each transfusion
  • The transfusion regimen is designed to obtain a pre-transfusion Hb concentration of 95-100 g/L.
  • Transfusions are usually given every two to three weeks.

Thalassemia intermedia. Treatment of individuals with thalassemia intermedia is symptomatic and based on splenectomy and folic acid supplementation.

  • Treatment of extramedullary erythropoietic masses is based on radiotherapy, transfusions, or, in selected cases, hydroxyurea (with a protocol similar to that used for sickle cell disease).
    Hydroxyurea also increases globin gamma chains and may have other undefined effects.
  • Individuals with thalassemia intermedia may develop iron overload from increased gastrointestinal absorption of iron or from occasional transfusions; chelation therapy with deferasirox has been demonstrated to be safe and effective in persons age ten years or older with a liver iron concentration ≥5 mg Fe/g dry weight or serum ferritin ≥800 ng/mL (thresholds after which the risk of serious iron-related morbidity is increased) [Taher et al 2012].

Bone marrow transplantation

  • Bone marrow transplantation (BMT) from an HLA-identical sib represents an alternative to traditional transfusion and chelation therapy. If BMT is successful, iron overload may be reduced by repeated phlebotomy, thus eliminating the need for iron chelation.
  • The outcome of BMT is related to the pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis, and magnitude of iron accumulation. In children who lack the above risk factors, disease-free survival is higher than 90%. Adults with beta-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival of 80% and a two-year event-free survival of 76% with current treatment protocol [Baronciani et al 2016].
  • BMT from unrelated donors has been carried out on a limited number of individuals with β-thalassemia. Provided that selection of the donor is based on stringent criteria of HLA compatibility and that individuals have limited iron overload, results are comparable to those obtained when the donor is a compatible sib [La Nasa et al 2005, Gaziev et al 2013].
  • Severe acute graft-vs-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor.
  • Affected individuals without matched donors could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [Sodani et al 2011, Anurathapan et al 2016].

Cord blood transplantation. Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk for GVHD [Pinto & Roberts 2008]. For couples who have already had a child with thalassemia and who undertake prenatal diagnosis in a subsequent pregnancy, prenatal identification of HLA compatibility between the affected child and an unaffected fetus allows collection of placental blood at delivery and the option of cord blood transplantation to cure the affected child [Orofino et al 2003]. Alternatively, in case of an affected fetus and a previous unaffected child, the couple may decide to continue the pregnancy and pursue BMT later, using the unaffected child as the donor.

Unrelated cord blood transplantation has been explored as an alternative option for affected individuals without a suitable HLA-matched unrelated adult donor. However, this strategy may be limited by less-than-adequate cell dose and higher rates of primary graft failure. One potential strategy may be the use of two cord blood units in order to achieve the desired cell dose, as has been done in individuals with malignancy – although this approach may be associated with a higher rate of acute GVHD, which may add to the burden of morbidity and mortality for this population.

For these reasons, unrelated cord blood transplantation would appear to be a suboptimal strategy for individuals with thalassemia [Ruggeri et al 2011]. However, others have found the outcome of unrelated cord blood transplantation to be more favorable. Jaing et al [2012] reported an overall survival of 88% and a thalassemia-free survival of 74% in 35 individuals with β-thalassemia.

Prevention of Primary Manifestations

Early detection of anemia, the primary manifestation of the disease, allows early appropriate treatment and monitoring.

Prevention of Secondary Complications

Transfusional Iron Overload

The most common secondary complications are those related to transfusional iron overload, which can be prevented by adequate iron chelation.

Assessment of iron overload

  • Serum ferritin concentration. In clinical practice, the effectiveness of chelators is monitored by routine determination of serum ferritin concentration. However, serum ferritin concentration is not always reliable for evaluating iron burden because it is influenced by other factors, the most important being the extent of liver damage.
  • Liver biopsy. Determination of liver iron concentration in a liver biopsy specimen shows a high correlation with total body iron accumulation and is the gold standard for evaluation of liver iron overload. However, (1) liver biopsy is an invasive technique involving the possibility (though low) of complications; (2) liver iron content can be affected by hepatic fibrosis, which commonly occurs in individuals with iron overload and hepatitis C virus infection; and (3) irregular iron distribution in the liver can lead to false negative results [Clark et al 2003].
  • Magnetic biosusceptometry (SQUID), which gives a reliable measurement of hepatic iron concentration, is another option [Fischer et al 2003]; however, magnetic susceptometry is presently available only in a limited number of centers worldwide.
  • MRI techniques for assessing iron loading in the liver and heart are commonly used [Pennell 2005, Wood 2008]. T2 and T2* parameters have been validated for liver iron concentration. Cardiac T2* is reproducible, is applicable between different scanners, correlates with cardiac function, and relates to tissue iron concentration [Pennell 2005, Wood 2008]. Clinical utility of T2* in monitoring individuals with siderotic cardiomyopathy has been demonstrated. In one study, 12 human hearts from transfusion-dependent affected individuals after either death or transplantation for end-stage heart failure underwent cardiovascular magnetic resonance R2* (the reciprocal of T2*) measurement. Tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy, providing calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration and detailing the iron distribution throughout the heart in iron overload [Carpenter et al 2011].

Chelation therapy

  • Desferrioxamine B (DFO). The first chelator introduced clinically was desferrioxamine B (DFO) administered five to seven days a week by 12-hour continuous subcutaneous infusion via a portable pump. Recommended dosage depends on the individual's age and the serum ferritin concentration. Young children start with 20-30 mg/kg/day, increasing up to 40 mg/kg/day after age five to six years. The maximum dose is 50 mg/kg/day after growth is completed. The dose may be reduced if serum ferritin concentration is low. By maintaining the total body iron stores below critical values (i.e., hepatic iron concentration <7.0 mg per gram of dry weight liver tissue), desferrioxamine B therapy prevents the secondary effects of iron overload, resulting in a consistent decrease in morbidity and mortality [Borgna-Pignatti et al 2004].
    • Ascorbate repletion (daily dose ≤100-150 mg) increases the amount of iron removed after DFO administration.
    • Side effects of DFO chelation therapy are more common in the presence of relatively low iron burden and include ocular and auditory toxicity, growth restriction, and, rarely, renal impairment and interstitial pneumonitis. DFO administration also increases susceptibility to Yersinia infections. The major drawback of DFO chelation therapy is low compliance resulting from complications of administration.
  • Deferiprone, a bidentated oral chelator, is administered in a dose of 75-100 mg/kg/day. The main side effects of deferiprone therapy include arthropathy, gastrointestinal symptoms, and, above all, neutropenia and agranulocytosis [Galanello & Campus 2009] that demand close monitoring. The effect of deferiprone on liver iron concentration may vary among the individuals treated. However, results from independent studies suggest that deferiprone is more cardioprotective than desferrioxamine: compared to those being treated with DFO, individuals being treated with deferiprone have better myocardial MRI pattern and less probability of developing (or worsening pre-existing) cardiac disease [Anderson et al 2002, Piga et al 2003]. These retrospective observations have been confirmed in a prospective study [Pennell et al 2006].
  • Deferasirox was developed as a once-daily oral monotherapy for the treatment of transfusional iron overload. It is effective in adults and children and has a defined safety profile that is clinically manageable with appropriate monitoring. The most common treatment-related adverse events are gastrointestinal disorders, skin rash, and a mild, non-progressive increase in serum creatinine concentration [Cappellini 2008]. Cases of renal failure, hepatic failure, cytopenias, and gastrointestinal hemorrhage have been reported in the post-marketing phase. Provided adequate doses are given, there is a good response to deferasirox across the full range of baseline liver iron concentration values. Prospective data demonstrate the efficacy of deferasirox in improving myocardial T2* and in maintaining a normal left ventricle ejection fraction [Pennell et al 2012, Pennell et al 2014]. Deferasirox has not been evaluated in formal trials for affected individuals with symptomatic heart failure or low left-ventricle ejection fraction.
  • Combination therapies. Strategies of chelation using a combination of desferrioxamine and deferiprone have been effective in individuals with severe iron overload. Retrospective, prospective, and randomized clinical studies have shown that combined iron chelation with desferrioxamine and deferiprone rapidly reduces myocardial siderosis, improves cardiac and endocrine function, reduces liver iron and serum ferritin concentration, reduces cardiac mortality, and improves survival; toxicity is manageable [Tanner et al 2007, Galanello et al 2010].

An open-label single-arm prospective Phase II study evaluated combination deferasirox-desferrioxamine in patients with severe transfusional myocardial siderosis followed by optional switch to deferasirox (DFX) monotherapy when achieving mT2* >10 ms, demonstrating that this association is able to rapidly decrease liver iron accumulation in heavily loaded patients and to lower myocardial overload in one third of them [Aydinok et al 2015a].

Preliminary studies using in combination the two oral chelators deferasirox and deferiprone appear to be encouraging [Berdoukas et al 2010, Farmaki et al 2011, Voskaridou et al 2011, Elalfy et al 2015].

Cardiac Disease

Particular attention has been directed to the early diagnosis and treatment of cardiac disease because of its critical role in determining the prognosis of individuals with β-thalassemia. Assessment of myocardial siderosis by MRI techniques and monitoring of cardiac function combined with intensification of iron chelation can result in excellent long-term prognoses [Wood 2008, Kirk et al 2009, Chouliaras et al 2011].

Osteoporosis

Osteoporosis is a common complication in adults with thalassemia major or thalassemia intermedia [Voskaridou & Terpos 2008]. Its origin is multifactorial, making it difficult to manage. Treatment involves appropriate hormonal replacement, an effective regimen of transfusion and iron chelation, vitamin D administration, and regular physical activity. Sufficient evidence exists to support the use of bisphosphonates in the management of thalassemia-associated osteoporosis (to prevent bone loss and improve the bone mineral density). Further research is warranted to establish their anti-fracture efficacy and long-term safety [Giusti 2014]. Denosumab and strontium ranelate have each been evaluated in only a single study, while there are no data on the effects of anabolic agents [Chavassieux et al 2014, Yassin et al 2014]. However, since the origin of bone disease in thalassemia major is multifactorial and some of the underlying pathogenic mechanisms are still unclear, further research in this field is needed to allow for the design of optimal therapeutic measures [Skordis & Toumba 2011, Dede et al 2016].

Surveillance

A general timetable for clinical and laboratory evaluation in thalassemia major has been provided by the Thalassemia International Federation [Cappellini et al 2014] and is available at the TIF website.

For individuals with thalassemia major, follow up to monitor the effectiveness of transfusion therapy and chelation therapy and their side effects includes the following:

  • Monthly physical examination by a physician familiar with the affected individual and the disease
  • Every three months: assessment of liver function tests (serum concentration of ALT), determination of serum ferritin concentration, and assessment of growth and development (during childhood)
  • Annual
    • Ophthalmologic and audiologic examinations
    • Complete cardiac evaluation, and evaluation of thyroid, endocrine pancreas, parathyroid, adrenal, and pituitary function
    • Liver ultrasound evaluation and determination of serum alpha-fetoprotein concentration in adults with hepatitis C and iron overload for early detection of hepatocarcinoma
    • Bone densitometry to assess for osteoporosis in the adult
    • Liver and myocardial MRI
  • Regular gallbladder echography for early detection of cholelithiasis [Origa et al 2009], particularly in individuals with the Gilbert syndrome genotype (i.e., presence of the (TA)7/(TA)7 motif in the UGT1A promoter)
  • In patients on deferasirox: monitoring of serum creatinine, creatinine clearance, and/or plasma cystatin C levels prior to therapy, weekly in the first month after initiation or modification of therapy, and monthly thereafter. Hepatic function should be checked before the initiation of treatment, every two weeks during the first month, and monthly thereafter in these patients.
  • Monitoring of patient's neutrophil count every week and in case of infection in patients on deferiprone

Agents/Circumstances to Avoid

The following should be avoided:

  • Alcohol consumption, which in individuals with liver disease has a synergistic effect with iron-induced liver damage
  • Iron-containing preparations

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual as early as possible. Early detection of anemia, the primary manifestation of β-thalassemia, allows prompt, appropriate treatment and monitoring.

Evaluations can include:

  • Molecular genetic testing if the pathogenic variants in the family are known
  • Hematologic testing if the pathogenic variants in the family are not known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Provided that a multidisciplinary team is available, pregnancy is possible and safe, and usually has a favorable outcome in women with β-thalassemia. An increasing number of women with thalassemia major and thalassemia intermedia may, therefore, have children. While hypogonadotropic hypogonadism remains a common condition in thalassemia major, gonadal function is usually intact and fertility is usually retrievable following a closely monitored stimulation therapy.

Although larger and more detailed studies are needed, an increased risk for certain complications cannot yet be excluded. For example, women with thalassemia intermedia who had never previously received a blood transfusion or who had received a minimal quantity of blood are reported to be at risk for severe alloimmune anemia if blood transfusions are required during pregnancy [Origa et al 2010].

Therapies Under Investigation

Several studies in Hbb(th3/+) mice, which serve as a model of untransfused β-thalassemia, showed that the use of minihepcidins (small drug-like hepcidin agonists) ameliorates ineffective erythropoiesis, anemia, and iron overload when used either alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation [Ramos et al 2012, Casu et al 2016]. The first clinical trials are expected soon.

The efficacy of hydroxyurea treatment in individuals with thalassemia is still unclear. Hydroxyurea is used in persons with thalassemia intermedia to reduce extramedullary masses, to increase hemoglobin levels, and, in some cases, to improve leg ulcers [Levin & Koren 2011]. Hydroxyurea prevents hemolysis and hypercoagulability by modifying the defective hemoglobin synthesis and reducing thrombocytosis. A retrospective study found no pulmonary hypertension in 50 individuals with thalassemia intermedia treated with hydroxyurea for seven years [Karimi et al 2009, Taher et al 2010]. A good response, correlated with particular polymorphisms in the beta-globin cluster (i.e., C>T at -158 G gamma), has been reported in individuals with transfusion dependence [Bradai et al 2003, Yavarian et al 2004]. However, controlled and randomized studies are warranted to establish the role of hydroxyurea in the management of thalassemia syndromes.

Modulators of erythropoiesis, such as TGF-β-like molecules or inhibitors of JAK2, could soon revolutionize the treatment of β-thalassemia and related disorders.

  • Activins, members of the TGF-β family signaling, are key regulators of human hematopoiesis, modulating various cellular responses such as proliferation, differentiation, migration, and apoptosis. Modified activin type II receptors inhibiting signaling induced by some members of the TGF-β superfamily promote maturation of terminally differentiating erythroblasts. In thalassemic mice (Hbbth1/th1), they ameliorate hematologic parameters as well as comorbidities that develop as a consequence of the erythroid hyperplasia [Dussiot et al 2014, Suragani et al 2014]. Ongoing clinical studies are evaluating their role in reducing transfusion burden in thalassemia major and raising hemoglobin concentration in thalassemia intermedia.
  • The discovery that JAK2 plays an important role in the progression and exacerbation of ineffective erythropoiesis suggests that drugs inhibiting JAK2 activity could mitigate ineffective erythropoiesis and reverse splenomegaly. In fact, in preclinical studies it has been shown that a JAK2 inhibitor dramatically decreased the spleen size and modulated the ineffective erythropoiesis [Breda & Rivella 2014]. A JAK2 inhibitor, ruxolitinib, has been tested to limit stress erythropoiesis in a Phase II clinical trial.

The possibility of correction of the molecular defect in hematopoietic stem cells by transfer of a normal gene via a suitable vector or by homologous recombination is being actively investigated. The most promising results in the mouse model have been obtained with lentiviral vectors [Persons 2009].

Several clinical trials of gene therapy for β-TM are ongoing in France, Italy, and the United States [Ferrari et al 2017]. One individual with transfusion-dependent HbE/β-thalassemia treated in France exhibited a therapeutic effect after transplantation with autologous CD34+ cells genetically modified with a β-globin lentiviral vector and had not required blood transfusions as of four years after the transplantation [Cavazzana-Calvo et al 2010]. Very encouraging preliminary data on individuals with HbE/β-thalassemia and homozygous β-thalassemia transplanted with autologous CD34+ cells transduced with a replication-defective, self-inactivating lentiviral vector containing an engineered HBB (βA-T87Q) were recently reported by the same group [Negre et al 2016].

Other approaches being investigated for gene therapy of the β-hemoglobinopathies include pharmacologic or genetic induction of γ-globin production through interference with the BCL11A pathway or disruption of the BCL11A erythroid enhancer by CRISPR/CAS9 technology as well as zinc finger or transcription activator–like effector nuclease, and even using genome editing in attempts at repairing the defective HBB in hematopoietic stem cells [Cottle et al 2016].

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The β-thalassemias are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry a single copy of an HBB pathogenic variant.
  • Heterozygotes (carriers) are clinically asymptomatic but occasionally slightly anemic. Carriers are often referred to as having thalassemia minor (or β-thalassemia minor).

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a clinically asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are clinically asymptomatic but occasionally slightly anemic. Carriers are often referred to as having thalassemia minor (or β-thalassemia minor).

Offspring of a proband

  • The offspring of an individual with β-thalassemia are obligate heterozygotes (carriers) for a pathogenic variant in HBB.
  • Because of the high carrier rate for β-thalassemia in certain populations (see Prevalence), the offspring of an affected individual and a reproductive partner from one of the high-prevalence areas are at increased risk for β-thalassemia.
  • Given the high carrier rate for β-thalassemia in these populations, it is appropriate to offer carrier testing to the partner of a proband with β-thalassemia.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an HBB pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives can be done by hematologic or molecular genetic testing.

Individuals who should be considered for carrier detection:

  • Family members
  • Gamete donors
  • Members of at-risk ethnic groups (see Table 4)

Hematologic testing. The carrier state is often referred to as β-thalassemia minor. Carriers are often identified by analysis of red blood cell indices (Table 1), which shows microcytosis (low MCV) and reduced content of Hb per red cell (low MCH), and by quantitative Hb analysis (Table 2), which displays HbA2 greater than 3.5%.

Pitfalls in carrier identification by hematologic testing:

  • Coinheritance of α-thalassemia, which may normalize the red blood cell indices. However, in α/β double heterozygotes, the HbA2 concentration remains in the β-thalassemia carrier range and thus is of diagnostic value.
  • Coinheritance of δ-thalassemia, which reduces to normal the increased HbA2 levels typical of the β-thalassemia carrier state. Double heterozygosity for δ- and β-thalassemia can be distinguished from the most common α-thalassemia carrier state by globin chain synthesis or globin gene analysis.
  • Confusion of α-thalassemia carriers with β-thalassemia carriers, resulting from microcytosis and hypochromia. However, α-thalassemia carriers are easily distinguished by normal HbA2 levels (see Alpha-Thalassemia).
  • Silent HBB variants – very mild pathogenic variants associated with consistent residual output of hemoglobin beta chains and with normal RBC indices and normal or borderline HbA2. However, homozygosity for silent pathogenic variants or compound heterozygosity for a silent HBB pathogenic variant and a typical HBB pathogenic variant result in mild non-transfusion-dependent forms of β-thalassemia.

Molecular genetic testing. When the hematologic analysis is abnormal, molecular genetic testing of HBB may be performed to identify the pathogenic variant, including mild and silent β-thalassemia pathogenic variants.

Population Screening

Individuals at increased risk. Because of the high carrier rate for HBB pathogenic variants in certain populations and the availability of genetic counseling and prenatal diagnosis, population screening is ongoing in several at-risk populations in the Mediterranean [Angastiniotis et al 2013]. Carrier testing relies on hematologic analysis. When the hematologic analysis indicates a β-thalassemia carrier state, molecular genetic testing of HBB can be performed to identify a pathogenic variant. If both partners of a couple have the HBB pathogenic variant, each of their offspring has a 1/4 risk of being affected. Through genetic counseling and the option of prenatal testing, such a couple can opt to bring to term only those pregnancies in which the fetus is unaffected.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

A thorough overview of the issues involved in thalassemia prevention is provided in Prevention of Thalassaemias and other Haemoglobin Disorders Volume 1 [Angastiniotis et al 2013] and Volume 2 [Harteveld et al 2012].

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once both HBB pathogenic variants have been identified in the couple at risk, prenatal testing and preimplantation genetic diagnosis are possible.

Prenatal diagnosis is available not only in cases of high-risk pregnancies but also in indeterminate-risk pregnancies.

An indeterminate-risk pregnancy is one in which:

  • One parent is a definite heterozygote and the other parent has a β-thalassemia-like hematologic picture, but no HBB pathogenic variant has been identified by sequence analysis;
  • The mother is a known heterozygote and the father is unknown or unavailable for testing, especially if the father belongs to a population at risk.

Options for noninvasive prenatal diagnosis:

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cooley's Anemia Foundation
    330 Seventh Avenue
    #900
    New York NY 10001
    Phone: 800-522-7222 (toll-free)
    Fax: 212-279-5999
    Email: info@cooleyanemia.org
  • My46 Trait Profile
  • NCBI Genes and Disease
  • Thalassaemia International Federation (TIF)
    PO Box 28807
    Nicosia 2083
    Cyprus
    Phone: +357 22 319129
    Fax: +357 22 314552
    Email: thalassaemia@cytanet.com.cy
  • National Haemoglobinopathy Registry
    MDSAS NHR Administrator
    5 Union Street
    City View House
    Manchester M12 4JD
    United Kingdom
    Phone: 0161 277 7917
    Email: support@mdsas.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Beta-Thalassemia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Beta-Thalassemia (View All in OMIM)

141900HEMOGLOBIN--BETA LOCUS; HBB
613985BETA-THALASSEMIA

Gene structure. HBB, which spans 1.6 kb, contains three exons and both 5' and 3' untranslated regions. HBB is regulated by an adjacent 5' promoter, which contains a TATA, CAAT, and duplicated CACCC boxes, and an upstream regulatory element dubbed the locus control region (LCR). A number of transcription factors regulate the function of HBB, the most important of which is the erythroid Kruppel-like factor (EKLF), which binds the proximal CACCC box. HBB is contained within the HBB gene cluster, which includes HBD, HBG1, HBG2, and an HBB pseudogene, HBBP1. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Almost 300 beta-thalassemia alleles have now been characterized (globin.cse.psu.edu). The large majority are missense, nonsense, or frameshift variants. Rarely, the β-thalassemias are the result of gross gene deletion. Classes of pathogenic variants:

  • βº-thalassemia (complete absence of hemoglobin subunit beta production) alleles resulting from nonsense, frameshift, or (sometimes) splicing variants
  • β+-thalassemia alleles (residual output of globin beta chains) resulting from pathogenic variants in intronic regions, the promoter area (either the CACCC or the TATA box), the polyadenylation signal, or the 5' or 3' untranslated region, or by splicing abnormalities
  • Complex β-thalassemias (delta-beta- and gamma-delta-beta-thalassemia) resulting from deletion of variable extent of the HBB gene cluster [Rooks et al 2005]
  • β-thalassemia caused by deletion of the LCR (leaving HBB intact) [Joly et al 2011]
  • Rarely, pathogenic variants outside the β-globin gene cluster (TFIIH and GATA-1)

Population-specific pathogenic variants are common (see Table 4), with four to ten variants usually accounting for most of the HBB pathogenic variants.

Note: Phenotypes of gamma-delta-beta-thalassemia and of β-thalassemia caused by deletion of the LCR in adult carriers (microcytic, hypocromic anemia with normal levels of HbA2) may be mistaken for alpha-thalassemia trait.

Table 4.

Selected HBB Pathogenic Variants

DNA Nucleotide Change 1
(Alias 2)
Predicted Protein Change 1
(Alias 2)
At-Risk PopulationsDetection FrequencyReference Sequences
c.-136C>G
(-87C>G)
--Mediterranean91%-95%NM_000518​.4
c.92+1G>A
(IVS1-1G>A)
--
c.92+6T>C
(IVS1-6T>C)
--
c.93-21G>A
(IVS1-110G>A)
--
c.118C>T
(cd39C>T)
p.Gln40Ter
(p.Gln39Ter)
c.316-106C>G
(IVS2-745C>G)
--
c.25_26delAA
(cd8-AA)
Lys9ValfsTer14
(p.Lys8ValfsTer13)
Middle East
c.27dupG
(cd8/9+G)
Ser10ValfsTer14
(p.Ser9ValfsTer13)
c.92+5G>C
(IVS1-5G>C)
--
c.118C>T
(cd39C>T)
p.Gln40Ter
(p.Gln39Ter)
c.135delC
(cd44-C)
Phe46LeufsTer16
(p.Phe45LeufsTer15)
c.315+1G>A
(IVS2-1G>A)
--
c.-78A>G
(-28A>G)
--Thai
c.52A>T
(17A>T)
p.Lys18Ter
(p.Lys17Ter)
c.59A>G
(19A>G)
p.Asn20Ser
(p.Asn19Ser)
(Hb Malay)
c.92+5G>C
(IVS1-5G>C)
--
c.126_129delCTTT
(c.124_127delTTCT)
(41/42-TTCT)
Phe42LeufsTer19
(p.Phe42LeufsTer17)
c.316-197C>T
(IVS2-654C>T)
--
c.-78A>G
(-28A>G)
--Chinese
c.52A>T
(17A>T)
p.Lys18Ter
(p.Lys17Ter)
c.126_129delCTTT
(c.124_127delTTCT)
(41/42-TTCT)
Phe42LeufsTer19
(p.Phe42LeufsTer17)
c.316-197C>T
(IVS2-654C>T)
--
c.-138C>T
(-88C>T)
--African / African American75%-80%
c.-79A>G
(-29A>G)
--
c.92+5G>C
(IVS1-5G>T)
--
c.75T>A
(cd24T>A)
p.Gly25=
(p.Gly24=)
c.316-2A>G
(IVS11-849A>G)
--
c.316-2A>C
(IVS11-849A>C)
--

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant nomenclature following current guidelines has been provided. However, because the initiation methionine is not part of the mature beta-globin protein, the longstanding convention of numbering the amino acids is to begin with the next amino acid (Val). For consistency with the literature and the Globin Gene Server (globin​.cse.psu.edu), the traditional amino acid numbering has been provided.

2.

Variant designation that does not conform to current naming conventions

Silent variants, which are characterized by normal hematologic findings and defined only by a mildly unbalanced α/β-globin chain synthesis ratio, result from pathogenic variants in the distal CACCC box, the 5' unbalanced region, the polyadenylation signal, and some splicing defects (see Table 5).

Table 5.

Mild and Silent HBB Pathogenic Variants Causing β-Thalassemia

Variant Type or LocationStandard Naming Conventions 1Aliases 2
DNA Nucleotide Change
(Predicted Protein Change)
Mild β+Silent
Transcriptional variants in the proximal CACC boxc.-140C>T
c.-138C>T
c.-138C>A
c.-137C>T
c.-137C>G
c.-137C>A
c.-136C>T
c.-136C>G
-90 C>T
-88 C>T
-88 C>A
-87 C>T
-87 C>G
-87 C>A
-86 C>T
-86 C>G
c.-151C>T
c.-142C>T
-101 C>T
-92 C>T
TATA boxc.-81A>G
c.-80T>A
c.-79A>G
-31 A>G
-30 T>A
-29 A>G
5' UTRc.-29G>A
c.-41de>T
c.-18C>G
+22 G>A
+10 -T
+33 C>G
c.-50A>C+1' A>C
Alternative splicingc.59A>G (p.Asn20Ser
(c.56A>G; p.Asn19Ser) 3
cd19 A>C
Hb Malay
c.72T>A (p.Gly25=)
(p.Gly24=) 3
cd24 T>A
c.82G>T (p.Ala28Ser)
(p.Ala27Ser) 3
cd27 G>T (Hb Knossos)
Consensus splicingc.92+6T>CIVS1-6 T>C
Intronc.316-7C>GIVS2-844 C>G
3' UTRc.*6C>G+6 C>G
Poly A sitec.*110T>C
c.*111A>G
AACAAA
AATGAA
c.*113A>GAATAAG
Mild βº (frameshift)c.20delA (p.Glu7GlyfsTer13)
(c.17delA; p.Glu6GlyfsTer12) 3
cd6-A
c.25_26delAA (p.Lys9ValfsTer14)
(p.Lys8ValfsTer13) 3
Cd8-AA

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Reference sequence is NM_000518 (www​.ncbi.nlm.nih.gov/Genbank).

2.

Nonstandard variant designations in common use (globin​.cse.psu.edu)

3.

Variant nomenclature following current guidelines has been provided. However, because the initiation methionine is not part of the mature beta-globin protein, the long-standing convention of numbering the amino acids is to begin with the next amino acid (Val). For consistency with the literature and the Globin Gene Server (globin​.cse.psu.edu), the traditional amino acid numbering has been provided in this table.

For more information, see Table A.

Normal gene product. HBB encodes hemoglobin subunit beta. The heterodimeric protein HbA is made up of two globin alpha chains and two globin beta chains.

Abnormal gene product. βº-thalassemia results from the absence of globin beta chains. In β+-thalassemia, the globin beta chain output is reduced to a variable extent, but the globin beta chains have a normal sequence.

References

Literature Cited

  • Allen S, Young E, Bowns B. Noninvasive prenatal diagnosis for single gene disorders. Curr Opin Obstet Gynecol. 2017;29:73–9. [PubMed: 28134670]
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Suggested Reading

  • Borgna-Pignatti C, Galanello R. Thalassemias and related disorders: quantitative disorders of hemoglobin synthesis. In: Greer JP, Foerster J, Rodgers GM, Paraskevas F, Glader B, Arber DA, Means RT, eds. Wintrobe’s Clinical Hematology. 12 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1083.
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  • Thuret I, Pondarré C, Loundou A, Steschenko D, Girot R, Bachir D, Rose C, Barlogis V, Donadieu J, de Montalembert M, Hagege I, Pegourie B, Berger C, Micheau M, Bernaudin F, Leblanc T, Lutz L, Galactéros F, Siméoni MC, Badens C. Complications and treatment of patients with β-thalassemia in France: results of the National Registry. Haematologica. 2010;95:724–9. [PMC free article: PMC2864377] [PubMed: 20007138]
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Chapter Notes

Author Notes

Antonio Cao, MD (1929-2012)

Antonio Cao, MD, Professor of Pediatrics at Cagliari University (Italy), was a world-renowned expert in the field of pediatrics and genetics. He was best known for his leadership role in understanding, diagnosing, preventing, and treating thalassemia. Among other honors, he received the Allan Award from the American Society of Human Genetics (1993) and the Märta Philipson's Award for Progress in Paediatrics, given by the Karolinska Institutet, Stockholm (2000). Professor Cao was passionate about science and new discoveries, intuitive, demanding, and extremely innovative in his research; all of us in this field – and our patients – are deeply indebted to him for his work and his inspiration will continue to guide us in the years ahead. – Renzo Galanello, MD

Renzo Galanello, MD (1948-2013)

Renzo Galanello, MD, Professor of Pediatrics at the University of Cagliari (Italy), was internationally recognized as an expert in the field of thalassemia, to which he contributed hundreds of papers. He was the right arm of his mentor Professor Antonio Cao in the program of thalassemia control in Sardinia. He defined the theoretical criteria, flow charts, and practical actuation of the carrier screening for thalassemia as a prerequisite to prenatal diagnosis. The efficacy of the screening, tightly linked to the development of improved methods of prenatal diagnosis, led to the near-eradication of beta-thalassemia in Sardinia, establishing a model of disease control that was adopted in numerous other countries worldwide. Lately, he was among the leading scientists in the clinical validation of novel oral chelators and diagnostic assessment of cardiac iron overload. Dr Galanello was a member of national and international scientific societies and editorial committees of hematology journals, and scientific advisor of the Thalassemia International Federation, which expressed well the sad feelings of his friends and colleagues with the following commemorative words: "Professor Galanello, you will be greatly missed, but indeed all you have left behind as a doctor and a person will never be forgotten, will remain in the books, in the literature, in our minds but very importantly in our hearts."

Author History

Antonio Cao, MD; Consiglio Nazionale delle Ricerche (2000-2012)
Renzo Galanello, MD; Ospedale Regionale Microcitemie (2000-2013)
Raffaella Origa, MD (2013-present)

Revision History

  • 25 January 2018 (ha) Comprehensive update posted live
  • 14 May 2015 (me) Comprehensive update posted live
  • 24 January 2013 (me) Comprehensive update posted live
  • 17 June 2010 (me) Comprehensive update posted live
  • 23 October 2007 (me) Comprehensive update posted to live Web site
  • 19 June 2005 (me) Comprehensive update posted to live Web site
  • 4 April 2003 (ac) Revision
  • 18 March 2003 (tk) Comprehensive update posted to live Web site
  • 28 September 2000 (me) Review posted to live Web site
  • March 2000 (ac) Original submission
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