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Synonyms: Cooley's Anemia, Mediterranean Anemia
, MD
Dipartimento di Sanità Pubblica e Medicina Molecolare
Università degli Studi di Cagliari
Ospedale Regionale per le Microcitemie
Cagliari, Italy

Initial Posting: ; Last Update: May 14, 2015.


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 only rarely requires transfusion. These individuals are at risk for iron overload secondary to increased intestinal absorption of iron as a result of ineffective erythropoiesis.


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. Biallelic pathogenic variants in HBB, the gene encoding the hemoglobin subunit beta, may be useful for diagnosis in at-risk individuals under age 12 months who have a positive or suggestive newborn screening result, a family history of β-thalassemia, and/or unexplained microcytic hypochromic anemia with nucleated red blood cells on peripheral blood smear.


Treatment of manifestations:

  • Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron. The only available definitive cure is bone marrow transplantation from a matched family or unrelated donor or cord blood transplantation from a related donor.
  • 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 primary manifestations: See Treatment of manifestations.

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); 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), and liver (ultrasound examination). 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 prenatal diagnosis has not been used and if the pathogenic allelic 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.

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 populations) is possible. Prenatal testing for pregnancies at increased risk is possible if the pathogenic allelic variants in the family are known.

GeneReview Scope

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


Suggestive Findings

Beta-thalassemia (β-thalassemia) major is 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., the finding of abnormal hemoglobin on isoelectric focusing or high-performance liquid chromatography on newborn blood spots)

Thalassemia intermedia is suspected in individuals who present at a later age with similar but milder clinical findings. Individuals with thalassemia intermedia only rarely require treatment with blood transfusion.

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), nucleated red blood cells on peripheral blood smear, and hemoglobin analysis that reveals decreased amounts of HbA and increased amounts of hemoglobin F (HbF) (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 nucleated red blood cells on peripheral blood smear
  • Biallelic pathogenic variants in HBB (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 (α2 β2)
  • Hemoglobin F (HbF): two globin alpha chains and two globin gamma chains (α2 γ2)
  • Hemoglobin A2 (HbA2): two globin alpha chains and two globin delta chains α2 δ2)

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

βº-thalassemia: complete absence of globin beta chain production


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 testing approaches can include targeted analysis for pathogenic variants or single-gene testing.

Targeted analysis for pathogenic variants based on ancestry may be considered first. The prevalent pathogenic variants are limited in each at-risk population (see Table 4).

Single-gene testing


Sequence analysis of HBB may be considered first if the affected individual is not of an ancestry that is high-risk or if targeted analysis reveals only one or no pathogenic variant.


Gene-targeted deletion/duplication analysis of HBB may be considered if only one or no pathogenic variant is found after sequence analysis has been performed.

Table 3.

Molecular Genetic Testing Used in Beta-Thalassemia

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
HBBTargeted analysis for pathogenic variants 3Variable depending on pathogenic variants included in panel and individual's ethnicity
Sequence analysis 499%
Gene-targeted deletion/duplication analysis 5Variable depending on individual's ethnicity

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


Pathogenic variants included in a panel may vary by laboratory.


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.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can 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.

Clinical Characteristics

Clinical Description

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. However, bone marrow examination is usually not necessary for diagnosis of affected individuals. 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.

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. Clinical presentation of thalassemia major occurs between ages six and 24 months. Affected infants fail to thrive and become progressively pale. 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.

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). Complications of iron overload in children include growth retardation and failure of sexual maturation and in adults include 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). In individuals who have been regularly transfused, iron overload results mainly from transfusions. Other complications are 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, and osteoporosis. The risk for hepatocellular carcinoma is increased secondary to liver viral infection, iron overload, and longer survival [Borgna-Pignatti et al 2004, Borgna-Pignatti et al 2014].

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 2014].

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 are growth retardation, pallor, jaundice, brown pigmentation of the skin, poor musculature, genu valgum, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. These skeletal changes include deformities of the long bones of the legs and typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency towards upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth), and osteoporosis. Individuals who have not been regularly transfused usually die before the third decade. 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 [Eldor & Rachmilewitz 2002, 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]. 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

Establishing genotype/phenotype correlations requires determination of the HBB pathogenic variants and assessment for coinheritance of those genetic determinants able to sustain a continuous production of gamma globin chains (HbF) in adulthood or able to reduce the alpha/non-alpha globin chain imbalance. Any inherited or acquired condition that reduces the alpha/non-alpha globin chain imbalance in β-thalassemia results in a lesser degree of alpha globin chain precipitation and leads to a mild β-thalassemia phenotype.

One of the most common and consistent mechanisms is homozygosity or compound heterozygosity for two β+-thalassemia mild and silent pathogenic variants (see Table 5).

In contrast, compound heterozygosity for a mild/silent β+ and a severe pathogenic variant produces a variable phenotype, ranging from thalassemia intermedia to thalassemia major. Therefore, the presence of this genotype does not predict a mild phenotype. Hemoglobin E (HbE), which is a thalassemic structural variant characterized by the presence of an abnormal structure as well as biosynthetic defect, should be included in this group. The nucleotide substitution at codon 26, producing the HbE variant (α2 β226 E>K), activates a potential cryptic RNA splice region, resulting in alternative splicing at this position. The homozygous state for HbE results in a mild hemolytic microcytic anemia. Compound heterozygosity for β-thalassemia and HbE results in a wide range of often severe but sometimes mild or even clinically asymptomatic clinical phenotypes.

The clinical picture resulting from homozygosity for β+-thalassemia or homozygosity for βº-thalassemia pathogenic variants may be ameliorated by coinheritance of pathogenic variants in the gene encoding the alpha globin chain associated with α-thalassemia, which reduces the output of the genes encoding the alpha globin chains and therefore decreases the alpha/non-alpha globin chain imbalance. Because coinherited α-thalassemia does not always produce a consistent effect, it cannot be used to predict phenotype.

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 variant per se increases the gamma globin chain (HbF) output. This occurs in the following two situations:
    • 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. The most common is a single-base substitution C to T at position 158 upstream of the transcription start site of HBG2, which is silent in normal individuals and in β-thalassemia heterozygotes, but leads to increased HbF production in individuals with erythropoietic stress, as occurs in homozygous β thalassemia. This HBG2 pathogenic variant, sometimes referred to as Gγ-158 C>T, is officially designated c.-210C>T. It is in linkage disequilibrium (in cis configuration) with some HBB variants (see Table 4 and Table 5). This explains the mild phenotype that may result from the inheritance of these pathogenic variants.
  • Coinheritance of heterocellular HPFH may or may not be linked to the HBB gene cluster. Studies using genome-wide association studies (G-WAS) have identified two quantitative trait loci (QTLs) (BCL11A on chromosome 2p16 and HBS1L-MYB intergenic region on chromosome 6q23) that account for 20%-30% of the common variation in HbF levels in healthy adults and persons with beta-thalassemia and sickle cell disease [Uda et al 2008, Thein et al 2009]. BCL11A appears to be involved in the regulation of the globin gene switching process [Sankaran et al 2008]. The ameliorating effect of QTLs and α-thalassemia on the phenotypic severity of homozygous β°-thalassemia has been reported [Galanello et al 2009]. Recently, an additional potential locus has been identified when single nucleotide variants in KLF1 were found to be associated with HPFH in a Maltese family and in a family from Sardinia [Borg et al 2010, Satta et al 2011]. KLF1 is a zinc-finger erythroid transcriptional regulator that binds to the critical promoter elements of the adult β-globin gene. It plays a critical role in regulating the switch between fetal and adult hemoglobin expression both by direct activation of β-globin and indirect repression of γ-globin gene expression in adult erythroid progenitors via regulation of BCL11A. Several KLF1 pathogenic variants have been identified in individuals with a thalassemia carrier phenotype and a particularly mild form of sickle cell disease [Gallienne et al 2012]. It is likely that many other HbF-associated QTLs also exist.

Other modifying factors. The clinical phenotype of homozygous β-thalassemia may also be modified by the coinheritance of other genetic factors mapping outside the β-globin gene cluster.

  • The best known of these modifying genes is UGT1A, the gene encoding uridin-diphosphoglucuronyltransferase. When combined with thalassemia major or thalassemia intermedia, the UGT1A pathogenic variant causing Gilbert disease (i.e., (TA)7 configuration instead of the (TA)6 in the TATA box) leads to increased jaundice and increased risk of gallstones [Origa et al 2009].
  • Genetic variations of the glutathione S-transferase M1 (GSTM1) enzyme seem to be associated with cardiac iron deposition and, in individuals with β-thalassemia major who have low body iron, the GSTM1-null genotype is a predisposing factor for myocardial iron overload, possibly due to enhanced entry of iron into the heart when GSTM1 is absent [Origa et al 2008].

Less defined modifying factors are genes coding for HFE-associated hereditary hemochromatosis and genes involved in bone metabolism.

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.
  • Compound heterozygosity for typical β-thalassemia pathogenic variants and the triple or (less frequently) quadruple alpha gene arrangement (αα/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 as causing thalassemia intermedia in association with the β-thalassemia carrier state [Harteveld et al 2008, Sollaino et al 2009].


β-thalassemia is prevalent in populations in the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and 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, in a limited part, 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 tricothiodystrophy) 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 very rare, so-called dominant β-thalassemias or thalassemic hemoglobinopathies result in an abnormal hyper-unstable protein product. The presence of hyper-unstable hemoglobin should be suspected in any individual with thalassemia intermedia when both parents are hematologically normal or in families with a pattern of autosomal dominant transmission of the thalassemia intermedia phenotype. HBB sequencing establishes the diagnosis.
  • 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.


Evaluations Following Initial Diagnosis

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
  • Hemoglobin level <7 g/dl on 2 occasions, > 2 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.

Treatment of Manifestations

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

Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron. Before starting the transfusions, it is absolutely necessary to carry out hepatitis B vaccination and perform 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 affects. 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 over 90%. Adults with beta-thalassemia are at a higher risk for transplant-related toxicity due to an advanced phase of the disease and have a cure rate of 65% with current treatment protocol [Isgrò et al 2010].
  • Chronic graft-versus-host disease (GVHD) of variable severity may occur in 5%-8% of individuals.
  • 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].
  • Affected individuals without matched donors could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [Sodani et al 2011].

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 graft versus host disease (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. However, 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 appears to be a suboptimal strategy for individuals with thalassemia [Ruggeri et al 2011]. However, others have found the outcome of this approach 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 HCV infection; and (3) irregular iron distribution in the liver can lead to possible 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, twelve 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 not to exceed 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 retardation, 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 (L-1), 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.

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 deferiprone and desferrioxamine 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].

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 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 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, calcium and 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]. 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].


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

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
  • 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 UGT1Apromoter)

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 older and younger sibs of a proband as early as possible. Early detection of anemia, the primary manifestation of β-thalassemia, allows prompt, appropriate treatment and monitoring.

  • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, hematologic testing can be used to clarify the disease status of at-risk sibs.

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. Although hypogonadotropic hypogonadism remains a common condition in thalassemia major, gonadal function is usually intact and fertility is usually retrievable.

Pregnancy also appears to be safe in most women with thalassemia intermedia, although larger and more detailed studies are needed. Indeed, 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

New chelation strategies are under investigation. A metabolic iron balance study in six affected individuals wherein the relative effectiveness of deferasirox (30 mg/kg/day) and deferoxamine (40 mg/kg/day) was compared, alone and in combination, demonstrated a negative iron balance in 5/6 using the combination of drugs just three days a week [Grady et al 2013]. This finding has been confirmed in some clinical studies [Arandi et al 2015]. Moreover, 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].

A study in a mouse model of hemochromatosis demonstrated that the use of minihepcidins (small drug-like hepcidin agonists) in a hepcidin-deficient mouse could be beneficial in iron overload disorders when used either alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation [Ramos et al 2012].

Induction of fetal hemoglobin synthesis can reduce the severity of β-thalassemia by improving the imbalance between alpha and non-alpha globin chains. Several pharmacologic compounds including 5-azacytidine, decytabine, and butyrate derivatives have had encouraging results in clinical trials [Pace & Zein 2006]. These agents induce Hb F by different mechanisms that are not yet well defined. Their potential in the management of β-thalassemia syndromes is under investigation [Perrine 2008, Boosalis et al 2011].

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. A modified activin type IIB receptor inhibiting signaling induced by some members of the TGF-β superfamily promotes maturation of terminally differentiating erythroblasts. In thalassemic mice (Hbbth1/th1), it ameliorates hematologic parameters as well as co-morbidities that develop as a consequence of the erythroid hyperplasia [Suragani et al 2014].
  • 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].

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].

A clinical trial for β-thalassemia has begun in France, and one individual with transfusion-dependent HbE/beta-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD 34(+) cells, genetically modified with a beta-globin lentiviral vector [Kaiser 2009]. The levels of genetically modified cells increased from 2% in the first few months to 11% at 33 months post transplant. The affected individual was last transfused on June 6, 2008, and four years after transplantation (despite being slightly anemic and undergoing repeated phlebotomies for the decrease of iron overload) does not require blood transfusions. Although most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 (a potential oncogene in various types of cancer) in erythroid cells, this integration seems hitherto benign [Cavazzana-Calvo et al 2010]. Very encouraging preliminary data on individuals with HbE/β-thalassemia and homozygous β-thalassemia transplantated with autologous CD34+ cells transduced with a replication-defective, self-inactivating lentiviral vector containing an engineered β-globin geneA-T87Q) were recently reported by the same group [Cavazzana et al 2014, Thompson et al 2014].

Search for access to information on clinical studies for a wide range of diseases and conditions.


Attempts at in utero transplantation using the father as a haploidentical donor have consistently failed.

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.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier of an HBB pathogenic variant is 2/3.
  • 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

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

Carrier Detection

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 Hb A2 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 mutations, i.e., 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 mutations or compound heterozygosity for a silent HBB mutation 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 is performed to identify the pathogenic variant. Mild and silent β-thalassemia pathogenic variants, which may result in attenuated forms of the disease, are identified and thus may lead to improved genetic counseling of couples at risk.

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 [Cao et al 2002]. 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 and Volume 2 [Old et al 2012, Old et al 2013].

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

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

High-risk pregnancies

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.
  • A mother is a known heterozygote and the father is unknown or unavailable for testing, especially if the father belongs to a population at risk.

In either instance, the options for prenatal testing should be discussed in the context of formal genetic counseling. In indeterminate-risk pregnancies, the prenatal testing strategy is analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation for the known HBB pathogenic variant. If the known HBB pathogenic variant is present, analysis of globin chain synthesis is performed on a fetal blood sample obtained by percutaneous umbilical blood sampling (PUBS) at approximately 18 to 21 weeks' gestation.


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
    New York NY 10001
    Phone: 800-522-7222 (toll-free)
    Fax: 212-279-5999
  • My46 Trait Profile
  • NCBI Genes and Disease
  • Thalassaemia International Federation (TIF)
    PO Box 28807
    Nicosia 2083
    Phone: +357 22 319129
    Fax: +357 22 314552
  • National Haemoglobinopathy Registry
    MDSAS NHR Administrator
    5 Union Street
    City View House
    Manchester M12 4JD
    United Kingdom
    Phone: 0161 277 7917

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, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

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


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 and whose knockout in mouse leads to a thalassemia-like clinical picture. HBB is contained within the HBB gene cluster, which also includes the genes encoding the delta globin chain, A gamma and G gamma chains, and an HBB pseudogene. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. β-thalassemias are heterogeneous at the molecular level. The β-thalassemias can be caused by more than 200 different HBB pathogenic variants [Huisman et al 1997,]. The large majority are simple single nucleotide substitutions or deletion or insertion of oligonucleotides leading to a frameshift. Rarely, the β-thalassemias are the result of gross gene deletion (frequency of deletions may vary across populations).

Despite marked molecular heterogeneity, the prevalent molecular defects are limited in each at-risk population (see Table 4), in which four to ten variants usually account for most of the HBB disease-causing alleles:

  • βº-thalassemia (complete absence of hemoglobin subunit beta production) alleles result from nonsense, frameshift, or (sometimes) splicing mutations.
  • β+-thalassemia alleles (residual output of globin beta chains) are produced by pathogenic variants in the promoter area (either the CACCC or the TATA box), the polyadenylation signal, or the 5' or 3' untranslated region, or by splicing abnormalities.
  • The complex β-thalassemias (delta-beta- and gamma-delta-beta-thalassemia) result from deletion of variable extent of the HBB gene cluster.
  • β-thalassemia may also be produced by deletion of the LCR, leaving intact HBB itself.
  • In rare instances, the β-thalassemia defect lies outside the β-globin gene cluster.

Table 4.

Selected HBB Pathogenic Variants

DNA Nucleotide Change 1
(Alias 2)
Protein Amino Acid Change 1At-Risk PopulationsDetection FrequencyReference Sequences
p.Lys8ValfsTer13Middle East
(Hb Malay)
--African / African American75%-80%

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 (www​ See Quick Reference for an explanation of nomenclature.


The DNA nucleotide change designations follow current nomenclature guidelines. However, because the initiating 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​, the amino acid numbering in this table follows that convention.


Variant designation that does not conform to current naming conventions

Silent mutations, which are characterized by normal hematologic findings and defined only by a mildly unbalanced α/β-globin chain synthesis ratio, result from mutation of 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

Mutation Type or LocationAliases 1Standard Naming Conventions 2
Mild β+SilentDNA Nucleotide Change
(Protein Amino Acid Change)
mutants in the proximal CACCbox
-90 C>T
-88 C>T
-88 C>A
-87 C>T
-87 C>G
-87 C>A
-86 C>T
-86 C>G
-101 C>T
-92 C>T
TATA box-31 A>G
-30 T>A
-29 A>G
5' UTR+22 G>A
+10 -T
+33 C>G
+1' A>Cc.-50A>C
Alternative splicingcd19 A>C (Hb Malay)
cd24 T>A
c.56A>G (p.Asn19Ser) 3
c.72T>A (p.Gly24Gly) 3
cd27 G>T (HbKnossos)c.82G>T (p.Ala27Ser) 3
Consensus splicingIVS1-6 T>Cc.91+6T>C
IntronIVS2-844 C>Gc.316-7C>G
3' UTR+6 C>Gc.*6C>G
Poly A siteAACAAA
Mild βºFrameshiftcd6-A
c.17delA (p.Glu6GlyfsTer12) 3
c.25_26delAA(p.Lys8ValfsTer13) 3

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 (www​ See Quick Reference for an explanation of nomenclature.


Nonstandard variant designations in common use (globin​


Reference sequence is NM_000518 (www​


The DNA nucleotide change designations follow current nomenclature guidelines. However, because the initiating 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​, the amino acid numbering in this table follows that convention.

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.


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Suggested Reading

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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

  • 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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Bookshelf ID: NBK1426PMID: 20301599


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