• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Beta-Thalassemia

Synonyms: Cooley's Anemia, Mediterranean Anemia. Includes: Thalassemia Major (Beta-Thalassemia Major), Thalassemia Intermedia, Thalassemia Minor (Beta-Thalassemia Minor, Heterozygous Beta-Thalassemia)

, MD, , MD, and , MD.

Author Information
, MD
Institute of Neurogenetics and Neuropharmacology
Consiglio Nazionale delle Ricerche
Cagliari, Italy
, MD
2nd Pediatric Clinic
University of Cagliari
Ospedale Regionale Microcitemie
Cagliari, Italy
, MD
Dipartimento di Sanità Pubblica e Medicina Molecolare
Università degli Studi di Cagliari
Ospedale Regionale per le Microcitemie
Cagliari,Italy

Initial Posting: ; Last Update: January 24, 2013.

Summary

Disease 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.

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. Molecular genetic testing of HBB, the gene encoding the hemoglobin subunit beta, may be useful for predicting the clinical phenotype in some cases as well as presymptomatic diagnosis of at-risk family members and prenatal diagnosis.

Management. 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, and folic acid supplementation.

Prevention of primary manifestations: See Treatment of manifestations.

Prevention of secondary complications: Prevention of transfusional iron overload by adequate iron chelation.

Surveillance: Thalassemia major: Monitoring of the effectiveness/side effects of transfusion therapy and chelation therapy in patients of all ages by monthly physical examination; bimonthly assessment of liver function tests; every three month determination of serum ferritin concentration; every six month evaluation of growth and development (during childhood); and 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.

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 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.

Diagnosis

Clinical Diagnosis

Thalassemia major is suspected in an infant or child younger than age two years with severe microcytic anemia, mild jaundice, and hepatosplenomegaly. Untreated, affected children usually manifest failure to thrive and expansion of the bone marrow to compensate for ineffective erythropoiesis.

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.

Testing

Hematologic Testing

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

Table 1. Red Blood Cell Indices in Beta-Thalassemia

Red Blood Cell IndexNormal 1 AffectedCarrier 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 1 AffectedCarrier
βº-Thal Homozygotes 2 β+-Thal Homozygotes or β+/βº Compound Heterozygotes 3 β-Thal Minor
HbA96%-98%010%-30%92%-95%
HbF<1%95%-98%70%-90%0.5%-4%
HbA2 2%-3%2%-5%2%-5%>3.5%

1. Data from Telen & Kaufman [1999]

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.

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.

In vitro synthesis of radioactive labeled globin chains in affected individuals reveals the following

  • βº-thalassemia: a complete absence of globin beta chains and a marked excess of globin alpha chains compared with globin gamma chains. The α/γ ratio is greater than 2.0.
  • β+-thalassemia: a variable degree of reduction of globin beta chains resulting in severe (thalassemia major) to mild (thalassemia intermedia) clinical phenotypes. The imbalance of the α/β and γ ratio is similar to that in βº-thalassemia major.

Molecular Genetic Testing

Gene. HBB is the only gene in which mutation is known to cause β-thalassemia (see Differential Diagnosis).

Clinical testing

The β-thalassemias can be caused by more than 200 different HBB pathogenic variants [Huisman et al 1997, globin.cse.psu.edu]; however, the prevalent molecular defects are limited in each at-risk population (see Table 4). This phenomenon has greatly facilitated molecular genetic testing. The principal molecular genetic testing used in beta-thalassemia is summarized in Table 3.

Table 3. Summary of Molecular Genetic Testing Used in Beta-Thalassemia

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
HBBTargeted mutation analysis Mutation panels vary by laboratoryVariable depending on mutations included in panel and individual's ethnicity
Sequence analysisSequence variants 4 99%
Deletion/duplication analysis 5Deletion of HBB or beta-globin gene clusterVariable depending on individual's ethnicity

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Typically, sequencing involves coding region and flanking intronic regions; mutations in the non-coding region and heterozygous deletions of an exon(s) or other gene region are not detected by this analysis. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

Confirmation of the diagnosis of beta-thalassemia in a proband requires identification of the pathogenic allelic variants in HBB. The appropriate order for molecular genetic testing:

1.

Targeted mutation analysis

2.

Sequence analysis

3.

Deletion/duplication analysis

Prognostication. Distinguishing thalassemia major from thalassemia intermedia at the molecular level for the purpose of prognostication requires defining of the HBB mutations and evaluating 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, such as alpha-thalassemia (see Genotype-Phenotype Correlations).

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of pathogenic variants in the family.

Clinical Description

Natural History

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. 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 rarely 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 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].

At present, prognosis for individuals who have been well transfused and treated with appropriate chelation is open-ended. Myocardial disease caused by transfusional siderosis is the most important life-limiting complication of iron overload in β-thalassemia. In fact, cardiac complications are reported to cause 71% of the deaths in individuals with β-thalassemia major [Borgna-Pignatti et al 2004].

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 (bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to a mongoloid slant of the eye, 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

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 mutations (see Table 5).

In contrast, compound heterozygosity for a mild/silent β+ and a severe mutation 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 mutations may be ameliorated by coinheritance of mutations 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 mutation per se increases the gamma globin chain (HbF) output. This occurs in the following two situations:
    • δβº-thalassemia is caused by deletions of variable size in the HBB gene cluster.
    • Deletions 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 point mutations of the hemoglobin Gγ (HBG2) or hemoglobin Aγ (HBG1) gene promoter. The most common is a single-base substitution C to T at position 158 upstream of the transcription start site of the HBG2 gene, 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 mutations.
  • Coinheritance of heterocellular HPFH may or may not be linked to the HBB gene cluster. Recent 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 seems 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 beta°-thalassemia has recently been reported [Galanello et al 2009]. Recently, an additional potential locus has been identified when point mutations 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. Recently, 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 mutation 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]. 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 mutations 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 mutations 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 mutations 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]

Prevalence

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 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.
  • 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

The initial step following diagnosis of β-thalassemia in an individual is to distinguish thalassemia intermedia from thalassemia major (see Testing Strategy). The diagnosis of thalassemia major implies the need for a regular transfusion program; the diagnosis of thalassemia intermedia implies the need for intermittent transfusions on an as-needed basis.

Treatment of Manifestations

A comprehensive review of the management of thalassemia major and thalassemia intermedia has been published by Thalassemia International Federation [Cappellini et al 2008] and is available at the TIF Web site (see www.thalassaemia.org.cy).

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 mechanisms. Because individuals with thalassemia intermedia may develop iron overload from increased gastrointestinal absorption of iron or from occasional transfusions, chelation therapy is started when the serum ferritin concentration exceeds 300 µg/L [Origa et al 2007].

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]. However, because of the limited number of individuals enrolled, further studies are needed to confirm these preliminary findings.
  • 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]. On the other hand, 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 seems to be a suboptimal strategy for individuals with thalassemia [Ruggeri et al 2011].

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. After ten to 12 transfusions, chelation therapy is initiated with 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.

In clinical practice, the effectiveness of DFO chelation therapy 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.

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 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].

In recent years, MRI techniques for assessing iron loading in the liver and heart have improved [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 a recent 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].

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.

Two other chelators have been introduced into clinical use: deferiprone and deferasirox.

  • Deferiprone (L-1), a bidentated oral chelator, available for several years in many countries, is administered in a dose of 75-100 mg/kg/day. The main side effects of deferiprone therapy include neutropenia, agranulocytosis, arthropathy, and gastrointestinal symptoms [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 may be 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].

    After many years of controversy, deferiprone is emerging as a useful iron chelator equivalent/alternative to desferrioxamine.
  • Deferasirox recently became available for clinical use in patients with thalassemia. 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]. Post-marketing experience and several phase IV studies will further evaluate the safety and efficacy of deferasirox.

New 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. In the past few years, 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. 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. Specific treatment with bisphosphonates has been attempted with promising results in several studies and confirmed in a randomized trial [Voskaridou et al 2008]. 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].

Surveillance

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 two months: assessment of liver function tests (serum concentration of ALT)
  • Every three months: determination of serum ferritin concentration
  • Every six months during childhood: assessment of growth and development
  • 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 UGT1A promoter)

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

If prenatal diagnosis has not been performed and if the disease-causing mutations have been identified in an affected family member, it is appropriate to offer molecular genetic testing to at-risk sibs to allow early diagnosis and appropriate treatment.

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 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 recent 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, has demonstrated a negative iron balance in 5/6 using the combination of drugs just three days a week [Grady et al 2013]. 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]. FBS0701, a novel, orally available member of the desazadesferrithiocin class of siderophore-related tridentate chelators, is currently in clinical development [Neufeld et al 2012].

A recent study in a mouse model of severe hemochromatosis has demonstrated that the use of minihepcidins, small drug-like hepcidin agonists, in a hepcidin-deficient mouse could be beneficial in iron overload disorders 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.

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. However, 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. Even if this integration seems hitherto benign, the ethical evaluation of risk/benefit ratios of gene therapy in thalassemia is difficult at present [Cavazzana-Calvo et al 2010].

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

Other

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 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 an 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 is 2/3.
  • Heterozygotes are clinically asymptomatic but occasionally slightly anemic. Carriers are often referred to as having thalassemia minor (or β-thalassemia minor).

Offspring of a proband

  • Each child of a proband inherits one copy of the HBB pathogenic variant from the affected parent and thus is an obligate heterozygote.
  • 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 of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

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 mutations 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 mutation 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 mutations, 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 mutations 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

A thorough overview of the issues involved in thalassemia prevention is provided in the Thalassemia International Federation publication Prevention of Thalassaemias and other Haemoglobin Disorders [Old et al 2012].

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

  • Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both pathogenic allelic variants must be identified before prenatal testing can be performed.
  • Preimplantation genetic diagnosis may be an option for some families in which the pathogenic variants have been identified.
  • Analysis of fetal cells in maternal blood. Prenatal diagnosis by analysis of fetal cells in maternal blood is being investigated [Kolialexi et al 2007]. However, the rarity of fetal erythroblasts in the maternal circulation limits the practicability of this approach [Traeger-Synodinos et al 2011].
  • Analysis of fetal DNA in maternal plasma for the presence of the father's mutation may lead to prenatal exclusion of homozygous β-thalassemia. This testing is being investigated with promising results [Tungwiwat et al 2007, Lun et al 2008, Hahn et al 2011, Lam et al 2012, Phylipsen et al 2012].

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 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation for the known HBB mutation. 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.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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
  • National Library of Medicine Genetics Home Reference
  • 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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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)

141900HEMOGLOBIN--BETA LOCUS; HBB
604131ALPHA-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 and whose knockout in the 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 Symbol.

Pathogenic allelic variants. β-thalassemias are heterogeneous at the molecular level. More than 200 pathogenic variants have been identified to date. 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 mutations 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 Populations Detection 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.Gln39Ter
c.316-106C>G
(IVS2-745C>G)
--
c.25_26delAA
(cd8-AA)
p.Lys8ValfsTer13Middle East
c.27_28insG
(cd8/9+G)
p.Ser9ValfsTer13
c.92+5G>C
(IVS1-5G>C)
--
c.118C>T
(cd39C>T)
p.Gln39Ter
c.135delC
(cd44-C)
p.Phe45LeufsTer15
c.315+1G>A
(IVS2-1G>A)
--
c.-78A>G
(-28A>G)
--Thai
c.52A>T
(17A>T)
p.Lys17Ter
c.59A>G
(19A>G)
p.Asn19Ser
(Hb Malay)
c.92+5G>C
(IVS1-5G>C)
--
c.124_127delTTCT
(41/42-TTCT)
p.Phe42LeufsTer17
c.316-197C>T
(IVS2-654C>T)
--
c.-78A>G
(-28A>G)
--Chinese
c.52A>T
(17A>T)
p.Lys17Ter
c.124_127delTTCT
(41/42-TTCT)
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.Gly24Gly
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 authors. 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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. 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​.cse.psu.edu), the amino acid numbering in this table follows that convention.

2. 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 Mutations Causing β-Thalassemia

Mutation Type or Location Aliases 1 Standard Naming
Conventions 2
Mild β+SilentDNA Nucleotide Change
(Protein Amino Acid Change)
Transcriptional
mutants in the proximal CACC box
-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.-140C>T
c.-138C>T
c.-138C>A
c.-137C>T
c.-137C>G
c.-137C>A
c.-136C>T
c.-136C>G
-101 C>T
-92 C>T
c.-151C>T
c.-142C>T
TATA box -31 A>G
-30 T>A
-29 A>G
c.-81A>G
c.-80T>A
c.-79A>G
5' UTR +22 G>A
+10 -T
+33 C>G
c.-29G>A
c.-41de>T
c.-18C>G
+1' A>Cc.-50A>C
Alternative splicing cd19 A>C (Hb Malay)
cd24 T>A
c.56A>G (p.Asn19Ser) 3
c.72T>A (p.Gly24Gly) 3
cd27 G>T (Hb Knossos)c.82G>T (p.Ala27Ser) 3
Consensus splicing IVS1-6 T>C c.91+6T>C
Intron IVS2-844 C>Gc.316-7C>G
3' UTR +6 C>Gc.*6C>G
Poly A site AACAAA
AATGAA
c.*110T>C
c.*111A>G
AATAAGc.*113A>G
Mild βº Frameshift cd6-A
cd8-AA
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 authors. 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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

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

3. 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​.cse.psu.edu), 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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM, Pennell DJ. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia. Lancet. 2002;360:516–20. [PubMed: 12241655]
  2. Berdoukas V, Carson S, Nord A, Dongelyan A, Gavin S, Hofstra TC, Wood JC, Coates T. Combining two orally active iron chelators for thalassemia. Ann Hematol. 2010;89:1177–8. [PubMed: 20217085]
  3. Boosalis MS, Castaneda SA, Trudel M, Mabaera R, White GL, Lowrey CH, Emery DW, Mpollo MS, Shen L, Wargin WA, Bohacek R, Faller DV, Perrine SP. Novel therapeutic candidates, identified by molecular modeling, induce γ-globin gene expression in vivo. Blood Cells Mol Dis. 2011;47:107–16. [PMC free article: PMC3148318] [PubMed: 21641240]
  4. Borg J, Papadopoulos P, Georgitsi M, Gutiérrez L, Grech G, Fanis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Ijcken W, Ozgür Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patrinos GP, Philipsen S. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010;42:801–5. [PMC free article: PMC2930131] [PubMed: 20676099]
  5. Borgna-Pignatti C, Vergine G, Lombardo T, Cappellini MD, Cianciulli P, Maggio A, Renda D, Lai ME, Mandas A, Forni G, Piga A, Bisconte MG. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol. 2004;124:114–7. [PubMed: 14675416]
  6. Bradai M, Abad MT, Pissard S, Lamraoui F, Skopinski L, de Montalembert M. Hydroxyurea can eliminate transfusion requirements in children with severe beta-thalassemia. Blood. 2003;102:1529–30. [PubMed: 12702505]
  7. Cao A, Rosatelli MC, Monni G, Galanello R. Screening for thalassemia: a model of success. Obstet Gynecol Clin North Am. 2002;29:305–28. [PubMed: 12108831]
  8. Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev. 2008;22 Suppl 2:S35–41. [PubMed: 19059055]
  9. Cappellini MD, Cohen A, Eleftheriou A, Piga A, Porter J, Taher A. Guidelines for the Clinical Management of Thalassaemia. 2 ed. Thalassemia International Foundation; 2008. [PubMed: 24308075]
  10. Cappellini MD, Musallam KM, Poggiali E, Taher AT. Hypercoagulability in non-transfusion-dependent thalassemia. Blood Rev. 2012;26 Suppl 1:S20–3. [PubMed: 22631037]
  11. Carpenter JP, He T, Kirk P, Roughton M, Anderson LJ, de Noronha SV, Sheppard MN, Porter JB, Walker JM, Wood JC, Galanello R, Forni G, Catani G, Matta G, Fucharoen S, Fleming A, House MJ, Black G, Firmin DN, St Pierre TG, Pennell DJ. On T2* magnetic resonance and cardiac iron. Circulation. 2011;123:1519–28. [PMC free article: PMC3435874] [PubMed: 21444881]
  12. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chrétien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, Leboulch P. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010;467:318–22. [PMC free article: PMC3355472] [PubMed: 20844535]
  13. Chouliaras G, Berdoukas V, Ladis V, Kattamis A, Chatziliami A, Fragodimitri C, Karabatsos F, Youssef J, Karagiorga-Lagana M. Impact of magnetic resonance imaging on cardiac mortality in thalassemia major. J Magn Reson Imaging. 2011;34:56–9. [PubMed: 21608067]
  14. Clark PR, Chua-Anusorn W, St Pierre TG. Proton transverse relaxation rate (R2) images of liver tissue; mapping local tissue iron concentrations with MRI. Magn Reson Med. 2003;49:572–5. [PubMed: 12594762]
  15. Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood. 2002;99:36–43. [PubMed: 11756150]
  16. Farmaki K, Tzoumari I, Pappa C. Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications. Blood Cells Mol Dis. 2011;47:33–40. [PubMed: 21531154]
  17. Fischer R, Longo F, Nielsen P, Engelhardt R, Hider RC, Piga A. Monitoring long-term efficacy of iron chelation therapy by deferiprone and desferrioxamine in patients with beta-thalassaemia major: application of SQUID biomagnetic liver susceptometry. Br J Haematol. 2003;121:938–48. [PubMed: 12786807]
  18. Freson K, Matthijs G, Thys C, Mariën P, Hoylaerts MF, Vermylen J, Van Geet C. Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum Mol Genet. 2002;11:147–52. [PubMed: 11809723]
  19. Galanello R, Agus A, Campus S, Danjou F, Giardina PJ, Grady RW. Combined iron chelation therapy. Ann N Y Acad Sci. 2010;1202:79–86. [PubMed: 20712777]
  20. Galanello R, Campus S. Deferiprone chelation therapy for thalassemia major. Acta Haematol. 2009;122:155–64. [PubMed: 19907153]
  21. Galanello R, Melis MA, Ruggeri R, Addis M, Scalas MT, Maccioni L, Furbetta M, Angius A, Tuveri T, Cao A. Beta 0 thalassemia trait in Sardinia. Hemoglobin. 1979;3:33–46. [PubMed: 457422]
  22. Galanello R, Sanna S, Perseu L, Sollaino MC, Satta S, Lai ME, Barella S, Uda M, Usala G, Abecasis GR, Cao A. Amelioration of Sardinian beta0 thalassemia by genetic modifiers. Blood. 2009;114:3935–7. [PMC free article: PMC2925722] [PubMed: 19696200]
  23. Gallienne AE, Dréau HM, Schuh A, Old JM, Henderson S. Ten novel mutations in the erythroid transcription factor KLF1 gene associated with increased fetal hemoglobin levels in adults. Haematologica. 2012;97:340–3. [PMC free article: PMC3291586] [PubMed: 22102705]
  24. Grady RW, Galanello R, Randolph RE, Kleinert DA, Dessi C, Giardina PJ. Toward optimizing the use of deferasirox: potential benefits of combined use with deferoxamine. Haematologica. 2013;98:129–35. [PMC free article: PMC3533674] [PubMed: 22875626]
  25. Hahn S, Lapaire O, Tercanli S, Kolla V, Hösli I. Determination of fetal chromosome aberrations from fetal DNA in maternal blood: has the challenge finally been met? Expert Rev Mol Med. 2011;13:e16. [PMC free article: PMC3087311] [PubMed: 21542948]
  26. Harteveld CL, Refaldi C, Cassinerio E, Cappellini MD, Giordano PC. Segmental duplications involving the alpha-globin gene cluster are causing beta-thalassemia intermedia phenotypes in beta-thalassemia heterozygous patients. Blood Cells Mol Dis. 2008;40:312–6. [PubMed: 18249014]
  27. Huisman THJ, Carver MFH, Baysal E. A Syllabus of Thalassemia Mutations. Augusta, GA: The Sickle Cell Anemia Foundation; 1997.
  28. Isgrò A, Gaziev J, Sodani P, Lucarelli G. Progress in hematopoietic stem cell transplantation as allogeneic cellular gene therapy in thalassemia. Ann N Y Acad Sci. 2010;1202:149–54. [PubMed: 20712786]
  29. Kaiser J. Gene therapy. Beta-thalassemia treatment succeeds, with a caveat. Science. 2009;326:1468–9. [PubMed: 20007873]
  30. Karimi M, Borzouee M, Mehrabani A, Cohan N. Echocardiographic finding in beta-thalassemia intermedia and major: absence of pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol. 2009;82:213–8. [PubMed: 19077048]
  31. Kirk P, Roughton M, Porter JB, Walker JM, Tanner MA, Patel J, Wu D, Taylor J, Westwood MA, Anderson LJ, Pennell DJ. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation. 2009;120:1961–8. [PMC free article: PMC2784198] [PubMed: 19801505]
  32. Kolialexi A, Vrettou C, Traeger-Synodinos J, Burgemeister R, Papantoniou N, Kanavakis E, Antsaklis A, Mavrou A. Noninvasive prenatal diagnosis of beta-thalassaemia using individual fetal erythroblasts isolated from maternal blood after enrichment. Prenat Diagn. 2007;27:1228–32. [PubMed: 17987605]
  33. La Nasa G, Argiolu F, Giardini C, Pession A, Fagioli F, Caocci G, Vacca A, De Stefano P, Piras E, Ledda A, Piroddi A, Littera R, Nesci S, Locatelli F. Unrelated bone marrow transplantation for beta-thalassemia patients: The experience of the Italian Bone Marrow Transplant Group. Ann N Y Acad Sci. 2005;1054:186–95. [PubMed: 16339665]
  34. Lam KW, Jiang P, Liao GJ, Chan KC, Leung TY, Chiu RW, Lo YM. Noninvasive prenatal diagnosis of monogenic diseases by targeted massively parallel sequencing of maternal plasma: application to β-thalassemia. Clin Chem. 2012;58:1467–75. [PubMed: 22896714]
  35. Levin C, Koren A. Healing of refractory leg ulcer in a patient with thalassemia intermedia and hypercoagulability after 14 years of unresponsive therapy. Isr Med Assoc J. 2011;13:316–8. [PubMed: 21845977]
  36. Lun FM, Tsui NB, Chan KC, Leung TY, Lau TK, Charoenkwan P, Chow KC, Lo WY, Wanapirak C, Sanguansermsri T, Cantor CR, Chiu RW, Lo YM. Noninvasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma. Proc Natl Acad Sci U S A. 2008;105:19920–5. [PMC free article: PMC2596743] [PubMed: 19060211]
  37. Neufeld EJ, Galanello R, Viprakasit V, Aydinok Y, Piga A, Harmatz P, Forni GL, Shah FT, Grace RF, Porter JB, Wood JC, Peppe J, Jones A, Rienhoff HY. A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload. Blood. 2012;119:3263–8. [PMC free article: PMC3321852] [PubMed: 22251482]
  38. Nemeth E, Ganz T. Hepcidin and iron-loading anemias. Haematologica. 2006;91:727–32. [PubMed: 16769573]
  39. Old J, Harteveld CL, Traeger-Synodinos J, Petrou M, Angastiniotis M, Galanello R. Prevention of Thalassaemias and other Haemoglobin Disorders. Volume 2: Laboratory Protocols. 2 ed. Thalassaemia International Federation Publications; 2012. [PubMed: 24672828]
  40. Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, Nemeth E. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007;92:583–8. [PubMed: 17488680]
  41. Origa R, Galanello R, Perseu L, Tavazzi D, Domenica Cappellini M, Terenzani L, Forni GL, Quarta G, Boetti T, Piga A. Cholelithiasis in thalassemia major. Eur J Haematol. 2009;82:22–5. [PubMed: 19021734]
  42. Origa R, Piga A, Quarta G, Forni GL, Longo F, Melpignano A, Galanello R. Pregnancy and beta-thalassemia: an Italian multicenter experience. Haematologica. 2010;95:376–81. [PMC free article: PMC2833066] [PubMed: 19903676]
  43. Orofino MG, Argiolu F, Sanna MA, Rosatelli MC, Tuveri T, Scalas MT, Badiali M, Cossu P, Puddu R, Lai ME, Cao A. Fetal HLA typing in beta thalassaemia: implications for haemopoietic stem-cell transplantation. Lancet. 2003;362:41–2. [PubMed: 12853199]
  44. Pace BS, Zein S. Understanding mechanisms of gamma-globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction. Dev Dyn. 2006;235:1727–37. [PubMed: 16607652]
  45. Pennell DJ. T2* magnetic resonance and myocardial iron in thalassemia. Ann N Y Acad Sci. 2005;1054:373–8. [PubMed: 16339685]
  46. Pennell DJ, Berdoukas V, Karagiorga M, Ladis V, Piga A, Aessopos A, Gotsis ED, Tanner MA, Smith GC, Westwood MA, Wonke B, Galanello R. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood. 2006;107:3738–44. [PubMed: 16352815]
  47. Perrine SP. Fetal globin stimulant therapies in the beta-hemoglobinopathies: principles and current potential. Pediatr Ann. 2008;37:339–46. [PubMed: 18543545]
  48. Persons DA. Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders. Hematology Am Soc Hematol Educ Program. 2009:690–7. [PubMed: 20008255]
  49. Phylipsen M, Yamsri S, Treffers EE, Jansen DT, Kanhai WA, Boon EM, Giordano PC, Fucharoen S, Bakker E, Harteveld CL. Non-invasive prenatal diagnosis of beta-thalassemia and sickle-cell disease using pyrophosphorolysis-activated polymerization and melting curve analysis. Prenat Diagn. 2012;32:578–87. [PubMed: 22517437]
  50. Piga A, Gaglioti C, Fogliacco E, Tricta F. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica. 2003;88:489–96. [PubMed: 12745268]
  51. Pinto FO, Roberts I. Cord blood stem cell transplantation for haemoglobinopathies. Br J Haematol. 2008;141:309–24. [PubMed: 18307566]
  52. Ramos E, Ruchala P, Goodnough JB, Kautz L, Preza GC, Nemeth E, Ganz T. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 2012;120:3829–36. [PMC free article: PMC3488893] [PubMed: 22990014]
  53. Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, Wingard JR, Fasth A, Lo Nigro L, Ayas M, Purtill D, Boudjedir K, Chaves W, Walters MC, Wagner J, Gluckman E, Rocha V. Eurocord Registry; Center for International Blood and Marrow Transplant Research; New York Blood Center. Umbilical cord blood transplantation for children with thalassemia and sickle cell disease. Biol Blood Marrow Transplant. 2011;17:1375–82. [PMC free article: PMC3395002] [PubMed: 21277376]
  54. Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, Mikkola HK, Hirschhorn JN, Cantor AB, Orkin SH. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322:1839–42. [PubMed: 19056937]
  55. Satta S, Perseu L, Moi P, Asunis I, Cabriolu A, Maccioni L, Demartis FR, Manunza L, Cao A, Galanello R. Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin. Haematologica. 2011;96:767–70. [PMC free article: PMC3084925] [PubMed: 21273267]
  56. Skordis N, Toumba M. Bone disease in thalassaemia major: recent advances in pathogenesis and clinical aspects. Pediatr Endocrinol Rev. 2011;8 Suppl 2:300–6. [PubMed: 21705982]
  57. Sodani P, Isgrò A, Gaziev J, Paciaroni K, Marziali M, Simone MD, Roveda A, De Angelis G, Gallucci C, Torelli F, Isacchi G, Zinno F, Landi F, Adorno G, Lanti A, Testi M, Andreani M, Lucarelli G. T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients. Pediatr Rep. 2011;3 Suppl 2:e13. [PMC free article: PMC3206538] [PubMed: 22053275]
  58. Sollaino MC, Paglietti ME, Perseu L, Giagu N, Loi D, Galanello R. Association of alpha globin gene quadruplication and heterozygous beta thalassemia in patients with thalassemia intermedia. Haematologica. 2009;94:1445–8. [PMC free article: PMC2754962] [PubMed: 19794088]
  59. Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, Saned MS, El-Chafic AH, Fasulo MR, Cappellini MD. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood. 2010;115:1886–92. [PubMed: 20032507]
  60. Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, Roughton M, Assomull R, Nair SV, Walker JM, Pennell DJ. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007;115:1876–84. [PubMed: 17372174]
  61. Telen MJ, Kaufman RE. The mature erythrocyte. In: Lee GR, Paraskevas F, Foerster J, Lukens J, eds. Wintrobe’s Clinical Hematology. 10 ed. Baltimore, MD: Lippincott Williams and Wilkins; 1999:207.
  62. Thein SL, Menzel S, Lathrop M, Garner C. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet. 2009;18:R216–23. [PMC free article: PMC2758709] [PubMed: 19808799]
  63. Traeger-Synodinos J, Vrettou C, Kanavakis E. Prenatal, noninvasive and preimplantation genetic diagnosis of inherited disorders: hemoglobinopathies. Expert Rev Mol Diagn. 2011;11:299–312. [PubMed: 21463239]
  64. Tungwiwat W, Fucharoen G, Fucharoen S, Ratanasiri T, Sanchaisuriya K, Sae-Ung N. Application of maternal plasma DNA analysis for noninvasive prenatal diagnosis of Hb E-beta-thalassemia. Transl Res. 2007;150:319–25. [PubMed: 17964521]
  65. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A. 2008;105:1620–5. [PMC free article: PMC2234194] [PubMed: 18245381]
  66. Viprakasit V, Gibbons RJ, Broughton BC, Tolmie JL, Brown D, Lunt P, Winter RM, Marinoni S, Stefanini M, Brueton L, Lehmann AR, Higgs DR. Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. Hum Mol Genet. 2001;10:2797–802. [PubMed: 11734544]
  67. Voskaridou E, Christoulas D, Konstantinidou M, Tsiftsakis E, Alexakos P, Terpos E. Continuous improvement of bone mineral density two years post zoledronic acid discontinuation in patients with thalassemia-induced osteoporosis: long-term follow-up of a randomized, placebo-controlled trial. Haematologica. 2008;93:1588–90. [PubMed: 18698086]
  68. Voskaridou E, Christoulas D, Terpos E. Successful chelation therapy with the combination of deferasirox and deferiprone in a patient with thalassaemia major and persisting severe iron overload after single-agent chelation therapies. Br J Haematol. 2011;154:654–6. [PubMed: 21615376]
  69. Voskaridou E, Terpos E. Pathogenesis and management of osteoporosis in thalassemia. Pediatr Endocrinol Rev. 2008;6 Suppl 1:86–93. [PubMed: 19337161]
  70. Wood JC. Cardiac iron across different transfusion-dependent diseases. Blood Rev. 2008;22 Suppl 2:S14–21. [PMC free article: PMC2896332] [PubMed: 19059052]
  71. Yavarian M, Karimi M, Bakker E, Harteveld CL, Giordano PC. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica. 2004;89:1172–8. [PubMed: 15477200]

Suggested Reading

  1. 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.
  2. Miller IJ, Bieker JJ. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins. Mol Cell Biol. 1993;13:2776–86. [PMC free article: PMC359658] [PubMed: 7682653]
  3. Modell B, Khan M, Darlison M, King A, Layton M, Old J, Petrou M, Varnavides L. A national register for surveillance of inherited disorders: beta thalassaemia in the United Kingdom. Bull World Health Organ. 2001;79:1006–13. [PMC free article: PMC2566700] [PubMed: 11731807]
  4. 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]
  5. Voskaridou E, Ladis V, Kattamis A, Hassapopoulou E, Economou M, Kourakli A, Maragkos K, Kontogianni K, Lafioniatis S, Vrettou E, Koutsouka F, Papadakis A, Mihos A, Eftihiadis E, Farmaki K, Papageorgiou O, Tapaki G, Maili P, Theohari M, Drosou M, Kartasis Z, Aggelaki M, Basileiadi A, Adamopoulos I, Lafiatis I, Galanopoulos A, Xanthopoulidis G, Dimitriadou E, Mprimi A, Stamatopoulou M, Haile ED, Tsironi M, Anastasiadis A, Kalmanti M, Papadopoulou M, Panori E, Dimoxenou P, Tsirka A, Georgakopoulos D, Drandrakis P, Dionisopoulou D, Ntalamaga A, Davros I, Karagiorga M. Greek Haemoglobinopathies Study Group.; A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births. Ann Hematol. 2012;91:1451–8. [PubMed: 22526366]

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

  • 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
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1426PMID: 20301599
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

  • Alpha-Thalassemia[GeneReviews<sup>®</sup>. 1993]
    Alpha-Thalassemia
    Origa R, Moi P, Galanello R, Cao A. GeneReviews<sup>®</sup>. 1993
  • Sickle Cell Disease[GeneReviews<sup>®</sup>. 1993]
    Sickle Cell Disease
    Bender MA, Hobbs W. GeneReviews<sup>®</sup>. 1993
  • Review Beta-thalassemia.[Orphanet J Rare Dis. 2010]
    Review Beta-thalassemia.
    Galanello R, Origa R. Orphanet J Rare Dis. 2010 May 21; 5:11. Epub 2010 May 21.
  • EPB42-Related Hereditary Spherocytosis[GeneReviews<sup>®</sup>. 1993]
    EPB42-Related Hereditary Spherocytosis
    Kalfa TA, Connor JA, Begtrup AH. GeneReviews<sup>®</sup>. 1993
  • Review Beta-thalassemia.[Genet Med. 2010]
    Review Beta-thalassemia.
    Cao A, Galanello R. Genet Med. 2010 Feb; 12(2):61-76.
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...