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Alpha-Thalassemia

, MD, , MD, , MD, and , MD.

Author Information
, MD
Dipartimento di Sanità Pubblica e Medicina Molecolare
Università degli Studi di Cagliari
Ospedale Regionale per le Microcitemie
Cagliari,Italy
, MD
Dipartimento di Sanità Pubblica e Medicina Molecolare
Università degli Studi di Cagliari
Ospedale Regionale per le Microcitemie
Cagliari,Italy
, MD
Dipartimento di Sanità Pubblica e Medicina Molecolare
Università degli Studi di Cagliari
Ospedale Regionale per le Microcitemie
Cagliari,Italy
, MD
Istituto di Ricerca Genetica e Biomedica
Consiglio Nazionale delle Ricerche
Cagliari, Italy

Initial Posting: ; Last Update: November 21, 2013.

Summary

Disease characteristics. Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease.

  • Hb Bart syndrome, the more severe form, is characterized by fetal onset of generalized edema, pleural and pericardial effusions, and severe hypochromic anemia, in the absence of ABO or Rh blood group incompatibility. Clinical features include: hepatosplenomegaly, extramedullary erythropoiesis, hydrocephaly, and cardiac and urogenital defects. Death usually occurs in the neonatal period.
  • HbH disease is characterized by microcytic hypochromic hemolytic anemia, hepatosplenomegaly, mild jaundice, and sometimes thalassemia-like bone changes.

Carriers of αº-thalassemia (α-thalassemia trait) show microcytosis, hypochromia, and normal percentages of HbA2 and HbF. Carriers of α+-thalassemia (α-thalassemia silent carrier) have either a silent hematologic phenotype or present with a moderate thalassemia-like hematologic picture. Homozygosity for α+-thalassemia results in an αº-thalassemia (α-thalassemia trait) hematologic phenotype.

Diagnosis/testing. All four α-globin alleles are deleted or inactivated in Hb Bart syndrome. Deletion or dysfunction of three alleles results in HbH disease. Alphaº-thalassemia results from deletion or dysfunction of two alleles, and α+-thalassemia results from deletion or dysfunction of one allele. Testing for α-thalassemia includes: hematologic testing of red blood cell indices, peripheral blood smear, supravital stain to detect RBC inclusion bodies, and qualitative and quantitative hemoglobin analysis. HBA1, the gene encoding α1-globin, and HBA2, the gene encoding α2-globin, are the two genes most commonly associated with α-thalassemia. Molecular genetic testing of HBA1 and HBA2 detects deletions in about 90% and point mutations in about 10% of affected individuals.

Management. Treatment of manifestations: No treatment is effective for Hb Bart hydrops fetalis. For HbH disease, occasional red blood cell transfusions may be needed during hemolytic or aplastic crises. Red blood cell transfusions are very rarely needed for severe anemia affecting cardiac function and erythroid expansion that results in severe bone changes and extramedullary erythropoiesis.

Prevention of primary manifestations: Prenatal diagnosis and early termination of pregnancies at risk for Hb Bart hydrops fetalis is usually considered because of the disease severity and risk for maternal complications.

Prevention of secondary complications: Monitor individuals with HbH disease for hemolytic/aplastic crisis during febrile episodes; in those who require chronic red blood cell transfusions, iron chelation therapy should be instituted; for those who are not red blood cell transfusion dependent, iron chelation with deferasirox can be considered to reduce liver iron concentration.

Surveillance: Hematologic evaluation every six to 12 months; assessment of growth and development in children every six to 12 months; monitoring of iron load with serum ferritin concentration and periodic quantitative measurement of liver iron concentration.

Agents/circumstances to avoid: In HbH disease, inappropriate iron therapy, oxidant drugs such as sulphonamides, and some antimalarials.

Evaluation of relatives at risk: Test the sibs of a proband as soon as possible after birth for HbH disease so that monitoring can be instituted.

Pregnancy management: Pregnant women with HbH disease are at risk for worsening anemia, preeclampsia, congestive heart failure, and threatened miscarriage; monitoring for these issues during pregnancy is recommended.

Genetic counseling. Alpha-thalassemia is usually inherited in an autosomal recessive manner. At conception, each sib of an individual with Hb Bart syndrome has a 25% chance of having Hb Bart syndrome, a 50% chance of having αº-thalassemia (α-thalassemia trait), and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her having αº-thalassemia (α-thalassemia trait) is 2/3.

At conception, if one parent has α°-thalassemia and the other is an α+-thalassemia silent carrier, each sib of an individual with HbH disease has a 25% chance of having HbH disease, a 25% chance of having αº-thalassemia (α-thalassemia trait), a 25% chance of having α+-thalassemia (α-thalassemia silent carrier), and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her having either αº-thalassemia (α-thalassemia trait) or α+-thalassemia (α-thalassemia silent carrier) is 2/3. Each child of an individual with HbH disease inherits the mutation for either αº-thalassemia or α+-thalassemia and is thus an obligate heterozygote; risk to the child for disease depends on the allele inherited from the other parent.

Family members, members of ethnic groups at risk, and gamete donors should be considered for carrier testing. Couples who are members of populations at risk for αº-thalassemia carrier status can be identified prior to pregnancy to identify those at risk of conceiving a fetus with Hb Bart syndrome. Prenatal testing may be carried out for couples who are at high risk of having a fetus with Hb Bart syndrome or for a pregnancy in which one parent is a known αº-thalassemia carrier when the other parent is either unknown or unavailable for testing.

GeneReview Scope

Alpha-Thalassemia: Included Disorders
  • Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome
  • Hemoglobin H (HbH) disease

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

Alpha-thalassemia (α-thalassemia) has two clinically significant forms:

Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome, the most severe form of α-thalassemia, is characterized by fetal onset of generalized edema, ascites, pleural and pericardial effusions, and severe hypochromic anemia, in the absence of ABO or Rh blood group incompatibility. It is usually detected by ultrasonography at 22 to 28 weeks' gestation and can be suspected in an at-risk pregnancy at 13 to 14 weeks' gestation when increased nuchal thickness, possible placental thickness, increased cerebral media artery velocity and increased cardiothoracic ratio are present. Death in the neonatal period is almost inevitable. All four α-globin alleles are deleted or dysfunctional (inactivated).

Hemoglobin H (HbH) disease should be suspected in an infant or child with a mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia and hepatosplenomegaly. Mild thalassemia-like bone changes are present in approximately one third of affected individuals. Unlike Hb Bart syndrome, HbH disease is compatible with survival into adulthood. HbH disease is a result of deletion or dysfunction of three of four α-globin alleles.

Alpha-thalassemia also has two carrier states:

  • Alphaº-thalassemia generally results from deletion or dysfunction of two α-globin genes, in cis (--/αα) (see Molecular Genetic Testing).
  • Alpha+-thalassemia usually results from deletion or dysfunction of one α-globin gene. Homozygosity for α+ thalassemia results in an α-thalassemia trait hematologic phenotype.

Testing

Hematologic Testing

Red blood cell indices show microcytic anemia in HbH disease or α-thalassemia trait; indices are usually normal in silent carriers and macrocytic in Hb Bart syndrome as a result of extreme reticulocytosis and megaloblastoid erythropoiesis (Table 1).

Table 1. Red Blood Cell Indices in Adults with Alpha-Thalassemia

Red Blood Cell IndicesNormalAffectedCarrier 1
MaleFemaleHemoglobin Bart hydrops fetalis 2Hemoglobin H disease 3Alpha-thalassemia trait 4
(--/αα or -α/-α)
Alpha-thalassemia silent carrier
Mean corpuscular volume (MCV, fl)89.1±5.0187.6±5.5136±5.1Children: 56±5
Adults: 61±4
71.6±4.181.2±6.9
Mean corpuscular hemoglobin (MCH, pg)30.9±1.930.2±2.131.9±918.4±1.222.9±1.326.2±2.3
Hemoglobin (Hb, g/dL)15.9±1.014.0±0.93-8Male: 10.9±1.0
Female: 9.5±0.8
Male: 13.9±1.7
Female: 12.0±1.0
Male: 14.3±1.4
Female: 12.6±1.2

1. Higgs & Bowden [2001]

2. Vaeusorn et al [1985]

3. Galanello et al [1992]

4. Alpha-thalassemia carriers with the two gene in cis (--/αα) genotype have slightly lower RBC indices.

Reticulocytosis

  • Hb Bart syndrome. Variable, may be more than 60%
  • HbH disease. Moderate, between 3% and 6%

Peripheral blood smear

  • Hb Bart syndrome. Large, hypochromic red cells and severe anisopoikilocytosis
  • HbH disease. Microcytosis, hypochromia, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells), and very rare nucleated red blood cells (i.e., erythroblasts)
  • Carriers. Reduced MCV, MCH, and RBC morphologic changes that are less severe than those in affected individuals; erythroblasts are not seen.

Supravital stain to detect RBC inclusion bodies. HbH inclusions (β4 tetramers) can be demonstrated in 5% to 80% of the erythrocytes of individuals with HbH disease following incubation of fresh blood smears with 1% brilliant cresyl blue (BCB) for four to 24 hours. Rare cells with inclusions can also be detected in subjects with α-thalassemia trait and the silent carrier state.

Qualitative and quantitative hemoglobin analysis (by cellulose acetate electrophoresis, weak-cation high-performance liquid chromatography [HPLC], and supplemental techniques such as isoelectric focusing and citrate agar electrophoresis) identifies the amount and type of Hb present. Hb types most relevant to α-thalassemia:

  • Hemoglobin A (HbA). Two α-globin chains and two β-globin chains (α2β2)
  • Hemoglobin H (HbH). Four β-globin chains (β4)
  • Hemoglobin Bart (Hb Bart). Four γ-globin chains (γ4)
  • Hemoglobin Portland. Two ζ-globin chains and two γ-globin chains (ζ2γ2)

The Hb pattern in α-thalassemia varies by α-thalassemia type (Table 2).

Table 2. Hemoglobin Patterns in Alpha-Thalassemia (Age >12 Months)

Hemoglobin TypeNormalAffectedCarrier
Hb Bart hydrops fetalis syndrome 1HbH disease 2Alpha-thalassemia trait 3Alpha-thalassemia silent carrier 4
HbA96%-98%060%-90%96%-98%96%-98%
HbF<1%0<1.0%<1.0%<1.0%
Hb Bart085%-90%2%-5%00
HbH000.8%-40%00
HbA2 2%-3%0<2.0%1.5%-3.0%2%-3%

1. Deletion or inactivation of all four α-globin chains makes it impossible to assemble HbF and HbA. Fetal blood contains mainly Hb Bart (γ4) and 10%-15% of the embryonic hemoglobin Portland (ζ2γ2).

2. Deletion or inactivation of three α-globin chains

3. Deletion or inactivation of two α-globin chains either in cis configuration (--/αα) or in trans configuration (-α/-α); also known as αº-thalassemia

4. Deletion or inactivation of one of the α-globin gene (-α/αα); also known as α+-thalassemia

In HbH disease, bone marrow is extremely cellular, mainly as a result of marked erythroid hyperplasia.

Note: Bone marrow examination is usually not necessary for diagnosis of affected individuals.

Newborn screening for sickle cell disease offered by several states/countries may detect Hb Bart in the newborn with α-thalassemia (see National Newborn Screening Status Report; pdf).

Notes: (1) Newborns with concentrations of Hb Bart greater than 15% need further evaluation (i.e., clinical and hematologic evaluation and molecular genetic testing), as they may develop HbH disease. (2) Low concentrations of Hb Bart (1%-8%) are indicative of the carrier states and usually do not need further evaluation. Reference ranges may very among laboratories performing newborn screening.

Molecular Genetic Testing

Genes. HBA1, encoding α1-globin, and HBA2, encoding α2-globin, are the two genes associated with α-thalassemia. They are localized to the telomeric region of chromosome 16p in a cluster containing the embryonically expressed HBZ encoding ζ-globin and a cis-acting regulatory element, HS-40, located 40 kb upstream of HBZ. All regulatory-element and trans-acting mutations causing α-thalassemia also ultimately alter expression of all these genes:

  • HBA1 is the α1 gene.
  • HBA2 is the α2 gene; it is 20 kb away from the embryonic ζ gene (Figure 1).
Figure 1

Figure

Figure 1. Diagram of the α-globin gene cluster. In order from centromere to telomere, the genes include: α1 (HBA1, encoding α1-globin); α2 (HBA2, encoding α2-globin); the pseudogenes ψα1, ψα2, (more...)

Clinical testing

    • Deletion of a single α-globin gene+-thalassemia mutations). Reciprocal recombination between the two chromosomes 16 either at the Z boxes (Figure 1), which are 3.7 kb apart, or the X boxes, which are 4.2 kb apart, deletes one α-globin gene. The two resulting deletions are referred to respectively as the 3.7-kb deletion (-α3.7) and the 4.2-kb deletion (-α4.2). Because they arise by recombination, these deletions are found in all populations. Note: Sometimes these are referred to as 3.7-kb rightward deletion and the 4.2-kb leftward deletion.

      In addition to these two common deletions, rare deletions involving a single α-globin gene have been reported.
    • Deletion of both α-globin genes on one chromosome (αº-thalassemia mutations). More than 20 different deletions ranging from approximately 6 kb to more than 300 kb and removing both α-globin genes (and sometimes embryonic HBZ) have been reported. The most common are −−SEA, −−FIL, −−MED, which in the homozygous state result in Hb Bart syndrome. When any of these alleles occur in combination with another allele carrying a single α-globin gene deletion (e.g., -α3.7), the result is HbH disease. These specific deletions are typically founder mutations.
    • Sequence variant HbConstant Spring (HbCS, c.427T>C), a common missense mutation of the termination codon of HBA2, leading to an elongated protein chain
  • Sequence analysis can be used to identify point mutations (including rare termination codon mutations and hyperunstable α-globin variants) in the coding regions of HBA1 and HBA2 when an α-globin deletion is not identified and suspicion for α-thalassemia is high [Traeger-Synodinos et al 2000].

    Note: A mutation in the HS-40 regulatory region located 40 kb upstream from the α-globin cluster, described in several pedigrees, would not be detected by DNA analysis of the alpha cluster region alone.
  • Deletion/duplication analysis can be used to detect common, rare, and/or novel deletions and duplications involving HBA1 and HBA2.

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

Gene 1Test MethodMutations Detected 2Percent of AllelesMutation Detection Frequency by Test Method 3
HBA1 and HBA2 Targeted mutation analysisCommon deletions 4 ~90% 5Variable 6
HBA2 Constant Spring 7Variable 6Variable 6
Sequence analysis 8HBA1, HBA2 sequence variants ~9%-10% Theoretically 100%
Deletion/duplication analysis 9Rare deletions and duplicationsUnknownVariable 6

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. May detect both deletions of a single α-globin gene or two α-globin gene deletions (either --/αα or -α/-α). Deletions detected may vary among laboratories.

5. Varies by population

6. Varies by population, testing laboratory, and test method

7. HbConstant Spring (HbCS), a common missense mutation of the termination codon of HBA2, leads to an elongated protein chain (see Table 4).

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

9. Testing that identifies exonic and whole-gene 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

See Figure 2 for a diagnostic algorithm for hemoglobinopathies.

Figure 2

Figure

Figure 2. Diagnostic algorithm for hemoglobinopathies

The following screening tests can be used if α-thalassemia is suspected:

  • Red blood cell indices
  • Peripheral blood smear
  • Red blood cell supravital stain of peripheral blood
  • Qualitative and quantitative hemoglobin analysis

To confirm the diagnosis in a proband, molecular genetic testing can be performed.

Carrier testing for at-risk relatives. Molecular genetic testing is requested in the parents of individuals with Hb Bart syndrome and HbH disease.

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 the pathogenic variants in the family.

Clinical Description

Natural History

The clinically significant phenotypes of alpha-thalassemia (α-thalassemia) are hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease. The severity of the α-thalassemia syndromes depends on the extent of α-globin chain defect (see Genotype-Phenotype Correlations).

Hb Bart syndrome is the most severe clinical condition related to α-thalassemia. Affected fetuses are either stillborn or die soon after birth. Red cells with Hb Bart have an extremely high oxygen affinity and are incapable of effective tissue oxygen delivery.

The clinical features are severe anemia, marked hepatosplenomegaly, diffuse edema, heart failure, and extramedullary erythropoiesis.

Developmental abnormalities, including hydrocephaly and cardiac and urogenital defects, have been reported.

Maternal complications during pregnancy commonly include: preeclampsia (hypertension, edema, and proteinuria), polyhydramnios (excessive amniotic fluid) or oligohydramnios (reduced amniotic fluid), antepartum hemorrhage, and premature delivery.

HbH disease. The phenotype of HbH disease varies [Chui et al 2003, Origa et al 2007]. Although clinical features usually develop in the first years of life, it may not present until adulthood or may be diagnosed only during routine hematologic analyses in asymptomatic individuals.

The majority of individuals show microcytic hypochromic hemolytic anemia (Table 1), enlargement of the spleen and less commonly the liver, mild jaundice, and sometimes mild-to-moderate thalassemia-like skeletal changes (such as hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) that mainly affect the facial features.

Individuals with HbH disease may develop hypersplenism and gallstones and experience acute episodes of hemolysis in response to oxidant drugs and infections.

While the majority of individuals with HbH disease have minor disability, some are severely affected, requiring regular blood transfusions; in very rare cases hydrops fetalis is present [Lorey et al 2001, Chui et al 2003].

Iron overload is uncommon but has been reported in older individuals, usually as a result of repeated blood transfusions or increased iron absorption.

Pregnancy is possible in women with HbH disease; however, worsening of anemia requiring blood transfusion has been reported [Origa et al 2007].

Genotype-Phenotype Correlations

The phenotype of the α-thalassemia syndromes depends on the degree of α-globin chain deficiency relative to β-globin production. The correlation between different α-thalassemia mutations, α-globin mRNA levels, α-globin synthesis, and clinical manifestations of α-thalassemia is well documented. The wide spectrum of hematologic and clinical phenotypes results from the presence and interaction of many α-thalassemia mutations.

The different α-thalassemia mutations vary widely in severity. The most and least severe (respectively) are: non-deletion HBA2, -α3.7 (because of compensatory increase of the α-globin gene output from the remaining HBA1) and non-deletion HBA1. For the -α4.2 deletion, evidence is inconclusive for a compensatory increase in the expression of the remaining α gene. The phenotype may be modified by triplication or quadruplication of the α-globin genes on one chromosome.

Alpha-thalassemia silent carrier results from a deletion or "non-deletion" mutation that inactivates one of the two α-globin genes (i.e., HBA1 or HBA2) on one chromosome+-thalassemia).

Non-deletion α+-thalassemia defects include the following:

  • Inactivating point mutations, including those important for gene expression (initiation codon mutation [HBA2:c.2T>C]); splicing sites (HBA2:c.95+2_95+6delTGAGG); termination codon HbConstant Spring
  • A frameshift caused by a deletion/insertion in the coding regions (i.e., (HBA2:c.94_95delAG), HBA2:c.[339C>G; 340_351delCTCCCCGCCGAG])
  • Rarely, very rapid post-synthetic degradation of a hyper-unstable α-globin variant. Non-deletion forms of α-thalassemia mainly occur in HBA2.

Carriers of α+ thalassemia may have a completely silent hematologic phenotype or may present with a moderate, thalassemia-like hematologic picture (i.e., reduced MCV and MCH, but normal HbA2 and HbF), similar to carriers of αº-thalassemia (see Alpha-thalassemia trait).

Alpha-thalassemia trait results from deletion or inactivation of two α-globin genes (--/αα in cis configuration or -α/-α in trans configuration). Carriers of αº-thalassemia show microcytosis (low MCV), hypochromia (low MCH), normal percentages of HbA2 and HbF, and RBC inclusion bodies.

Note: While the phenotype between cis configuration and trans configuration may not vary significantly, the genetic counseling implications are significant. See Genetic Counseling.

HbH disease results from deletion or inactivation of three α-globin genes, usually as a result of the compound heterozygous state for αº-thalassemia and α+-thalassemia. The phenotype of HbH disease (chronic microcytic, hypochromic hemolytic anemia of variable severity) mainly correlates with the severity of the α+-thalassemia defect:

  • Individuals with non-deletion HbH disease have a more severe phenotype with earlier presentation, more severe anemia, jaundice, bone changes, and greater hepatosplenomegaly. As a consequence of the more severe hematologic phenotype, they may need red cell transfusions more frequently than individuals with deletion HbH.
  • Individuals who are homozygous for non-deletion α-thalassemia defect (i.e., 2 of 4 α genes affected, but both with non-deletion mutations) may have HbH disease. For example, homozygotes for HbConstant Spring show a mild hemolytic anemia. Red blood cell indices are characterized by low red blood cell count, normal MCV, and slightly decreased MCV. Hb electrophoresis shows HbA - HbA2, HbConstant Spring (2.6%-11.6%), and Hb Bart.

Deletions of the HS-40 regulatory region found approximately 40 kb telomeric to HBZ (Figure 1) cause αº-thalassemia and have been reported in a few families with HbH disease [Higgs 2001]. The phenotype is like that of the deletion type of HbH disease.

Hb Bart syndrome results from deletion of four α-globin chains and rarely may involve non-deletion defects.

Nomenclature

The α-thalassemias are classified on the basis of the total globin production from each of the two α-globin genes present on each chromosome 16:

  • When both α-genes on a chromosome are deleted (--/αα) or inactivated, the condition is called α°-thalassemia (no output of α-globin from the chromosome). Previously, α° thalassemia was called α-thalassemia 1.
  • When one α-gene on a chromosome is deleted or inactivated by a mutation (i.e., non-deletion mutation) the condition is called α+ thalassemia (previously known as α-thalassemia 2). In this case, some α globin is produced. Non-deletion mutants are indicated as (αNDα/) or (αTα/).

Prevalence

Since the early 1960s, prevalence of α-thalassemia has been determined in several populations using the percent Hb Bart in cord blood. However, because not all newborns with α-thalassemia (mainly those with α+-thalassemia) have increased Hb Bart, the prevalence of α-thalassemia derived from this measure may be underestimated.

More precise data have been obtained using restriction endonuclease analysis. For detailed references for the frequency of α-thalassemia in each population, see Bernini [2001].

Africa

  • The highest gene frequency (0.30-0.40) of the -α3.7allele (causing α+-thalassemia) has been observed in the equatorial belt including Nigeria, Ivory Coast, and Kenya.
  • Alphaº-thalassemia has been reported very rarely in North Africa and in the African American population.

The Mediterranean

  • Alpha+-thalassemia (caused by the -α3.7allele) is common, with the highest frequency reported in Sardinia (0.18) and the lowest in Spain.
  • Alphaº-thalassemia is very rare (0.002); thus, Hb Bart hydrops fetalis is only rarely reported.
  • A remarkable aspect of α-thalassemia (mainly α+) in the Mediterranean population is the heterogeneity of mutations, particularly the non-deletion mutations.

The Arabian Peninsula

  • Gene frequencies of the -α3.7 allele (causing α+-thalassemia) vary from 0.01 to 0.67, with the highest values being observed in Oman.
  • Alphaº-thalassemia determinants are extremely rare.

India

  • Deletion α+-thalassemia reaches very high frequency (0.35-0.92) in the Indian tribal population of Andra Pradesh; in other tribes, the frequency is much lower (0.03-0.12). Both the -α3.7 allele and the -α4.2 allele variably contribute to the deletion α+-thalassemia.
  • Alphaº-thalassemia is very rare.

Southeast Asia

  • Alphaº-thalassemia (−−SEA, −−THAI, −−FIL) and α+-thalassemia are very common, causing a major public health burden.
  • The non-deletion form of α+-thalassemia, caused by the HbConstant Spring allele, is common.
  • The incidence of Hb Bart hydrops fetalis is expected to be between 0.5 and 5 per 1000 births and HbH disease between 4 and 20 per 1000 births.

Oceania

  • The distribution of α+-thalassemia, extensively studied by DNA-based methods, follows a pattern consistent with the degree of malaria endemicity. The prevalence of α+-thalassemia is low in the highlands and high in the coastal areas and the lowlands where malaria is hyperendemic.
  • Some alpha-thalassemias have unusual mutation mechanisms; for example, some affected individuals on the island of Vanuatu who have normal α-globin genes without deletions or mutations have a mutation in a regulatory element that creates a GATA-1 site and activates a cryptic promoter [De Gobbi et al 2006].
  • Alphaº-thalassemia is very rare.

Differential Diagnosis

Hydrops fetalis is associated with many conditions in addition to Hb Bart, including immune-related disorders (alloimmune hemolytic disease or Rh isoimmunization), fetal cardiac anomalies, chromosomal abnormalities, fetal infections, genetic disorders, and maternal and placental disorders. The combination of a hydropic fetus with a very high proportion of Hb Bart, however, is found in no other condition.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to Hb Bart, 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).

Hemoglobin H disease

  • Hemolytic anemias. HbH disease can be distinguished from other hemolytic anemias by: (1) microcytosis, which is uncommon in other forms of hemolytic anemia; (2) the fast-moving band (HbH) on hemoglobin electrophoresis; (3) the presence of inclusion bodies (precipitated HbH) in red blood cells after vital stain; and (4) absence of morphologic or enzymatic changes characteristic of other forms of inherited hemolytic anemia (e.g., hereditary spherocytosis/elliptocytosis, G6PD deficiency). See EPB42-Related Hereditary Spherocytosis.
  • Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by distinctive craniofacial features, genital anomalies, severe developmental delays, hypotonia, intellectual disability, and mild-to-moderate anemia secondary to alpha-thalassemia. Craniofacial abnormalities include small head circumference, telecanthus or ocular hypertelorism, small nose, tented upper lip, and prominent or everted lower lip with coarsening of the facial features over time. Although all individuals with ATRX syndrome have a normal 46,XY karyotype, genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female genitalia. Global developmental delays are evident in infancy, and some affected individuals never walk independently or develop significant speech. Affected individuals do not reproduce. Inheritance is X-linked.

    An unknown percent of 46,XY individuals with ATRX syndrome have a mild form of HbH disease, evident as hemoglobin H inclusions (β4 tetramers) in erythrocytes following incubation of fresh blood smears with 1% brilliant cresyl blue (BCB).

    Mutations in ATRX are causative. The ATR-X protein is a novel member of the SWI2/ SNF2 family of molecular motors that remodel chromatin using hydrolysis of ATP as a source of energy. The chromatin remodeling alters the access of DNA to trans-acting factors, thereby influencing transcription, replication, repair, and methylation and thus regulating the expression of a restricted class of genes including the α-globin genes [Picketts et al 1998, Higgs 2004].

    Note: In ATRX syndrome, the α-globin gene cluster and the HS-40 regulatory region of chromosome 16 are structurally intact.
  • Acquired mutations in ATRX can arise in myelodysplastic syndrome and cause an acquired form of HbH disease (See Genetically Related Disorders, Acquired α-thalassemia).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to HbH disease, go to Image SimulConsult.jpg.

Carrier states (αº-thalassemia and α+-thalassemia)

  • Beta-thalassemia. Whereas microcytosis and hypochromia are present in αº-thalassemia carriers, hematologically manifesting α+-thalassemia carriers, and β-thalassemia carriers, β-thalassemia carriers are distinguished by a high percent of HbA2.
  • Iron deficiency anemia
    • The αº-thalassemia carrier state and the hematologically evident forms of α+-thalassemia can be confused with iron-deficiency anemia because MCV and MCH are lower than normal in both conditions. However, in iron deficiency anemia, the red blood cell count is decreased, while it is usually increased in αº-thalassemia carriers.
    • Though some overlap with alpha-thalassemia carrier states exists, individuals with iron deficiency anemia show a marked increase in red blood cell distribution width (RDW), a quantitative measure of RBC anisocytosis. The RDW is usually normal or close to normal in thalassemia.
    • The determination of the RBC zinc protoporphyrin concentration and iron studies (serum iron concentration, transferrin saturation) can be used to diagnose iron deficiency anemia with certainty.
    • Iron deficiency and thalassemia can coexist, complicating diagnosis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to the following, go to Image SimulConsult.jpg:

Management

Guidelines for the management of HbH disease with hemolytic crisis have been developed [Fucharoen & Viprakasit 2009 (full text)].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with alpha-thalassemia (α-thalassemia), the following phenotype-based evaluations are recommended:

  • Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome. See Prenatal Testing.
  • Hemoglobin H (HbH) disease
    • Differentiation of deletion (mild) from non-deletion (moderate-to-severe) forms of HbH disease by appropriate molecular genetic testing of HBA1 and HBA2 is important at presentation because of varying severity.
    • Consider referral to a hematologist.
    • Consider referral to a medical geneticist or genetic counselor.

Treatment of Manifestations

Hb Bart syndrome currently has no effective treatment. However, in some cases noninvasive monitoring by Doppler ultrasonography, intrauterine transfusions, and hematopoietic stem cell transplantation (HSCT) have improved the prognosis of individuals with this disorder [Vichinsky 2009]. These advances in intrauterine and postnatal therapy have resulted in ethical dilemmas for the family and health care provider.

HbH disease

  • Most individuals with HbH disease are clinically well and survive without any treatment.
  • Occasional red blood cell transfusions may be needed if the hemoglobin level suddenly drops because of hemolytic or aplastic crises.
  • Chronic red blood cell transfusions should be considered in selected individuals only. Clear indications for red blood cell transfusions are severe anemia affecting cardiac function and massive erythroid expansion, resulting in severe bone changes and extramedullary erythropoiesis. Note: These events are quite rare in HbH disease.
  • Splenectomy should be performed only in case of massive splenomegaly or hypersplenism; but the risk of severe, life-threatening venous thrombosis should be considered.
  • Other complications, such as gallstones and leg ulcers, require appropriate medical or surgical treatment.

Prevention of Primary Manifestations

Hb Bart hydrops fetalis syndrome

  • Early treatment with intrauterine transfusions or in utero hematopoietic stem cell transplantation has been unsuccessful and also may be not be justified in view of the unknown future risks for normal development. In fact, affected neonates have marked cardiopulmonary problems and a high frequency of congenital malformations (patent ductus arteriosus, limb and genital abnormalities) in addition to the hematopoietic failure. In those infants surviving the immediate postnatal period, subsequent development has been abnormal. All infants require regular blood transfusions and iron chelation therapy. Given these results, further human experimentation should be discouraged until more effective therapies (e.g., somatic gene therapy) are available.
  • Because of the severity of Hb Bart hydrops fetalis syndrome and the risk for maternal complications during the pregnancy with a fetus with this disorder, prenatal diagnosis and early termination of affected pregnancies is usually considered.

Prevention of Secondary Complications

HbH disease

  • During febrile episodes, a clinical evaluation is recommended because of the increased risk of hemolytic/aplastic crisis (similar to G6PD deficiency, hemolysis in HbH disease can be triggered by infection or oxidative stresses).
  • When chronic red blood cell transfusions are instituted for individuals with HbH disease, the management should be the same as for all individuals who have been polytransfused, including use of iron chelation therapy (see Beta-Thalassemia).
  • In individuals with HbH disease who are not red blood cell transfusion dependent, the only iron chelator specifically approved is deferasirox, which was recently shown to be superior to placebo in reducing liver iron concentration in those greater than 10 years old who have beta thalassemia intermedia, Beta/E thalassemia and HbE disease [Taher et al 2012].
  • Some clinicians recommend folic acid supplementation, as for other hemolytic anemias.
  • If splenectomy is required, antimicrobial prophylaxis is usually provided, at least until age five years, to decrease the risk of overwhelming sepsis caused by encapsulated organisms. Use of antimicrobial prophylaxis notwithstanding, a careful clinical evaluation of splenectomized individuals with fever is recommended.

Surveillance

HbH disease

  • Hematologic evaluation every six to 12 months to determine the steady state levels of hemoglobin
  • In children, assessment of growth and development every six to 12 months
  • Monitoring of iron load with annual determination of serum ferritin concentration in individuals who have been transfused, in older individuals, and in those given inappropriate iron supplementation. Since serum ferritin may underestimate the degree of iron overload, a periodic quantitative measurement of liver iron concentration is also recommended [Musallam et al 2012].

Agents/Circumstances to Avoid

HbH disease

  • Inappropriate iron therapy
  • Oxidant drugs including sulphonamides; some antimalarials because of the risk of hemolytic crisis

Evaluation of Relatives at Risk

The sibs of a proband should be tested as soon as possible after birth to determine if they have HbH disease so that appropriate monitoring can be instituted.

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

Pregnancy Management

During pregnancy several complications have been reported in women with HbH disease, including worsening of anemia (with occasional need of red cell transfusions), preeclampsia, congestive heart failure, and threatened miscarriage [Origa et al 2007]. Monitoring for these possible complications is recommended.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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

Alpha-thalassemia (α-thalassemia) is usually inherited in an autosomal recessive manner.

Risk to Family Members — Hemoglobin Bart Hydrops Fetalis (Hb Bart) Syndrome

Parents of a proband

  • The parents of a fetus with Hb Bart hydrops fetalis are obligate heterozygotes for two α-globin gene deletions (αº-thalassemia or α-thalassemia trait).
  • Individuals with α-thalassemia trait typically have mild hypochromia (low MCH) microcytosis (low MCV) anemia and normal HbA2 and HbF.

Sibs of a proband

  • At conception, each sib of a proband with Hb Bart hydrops fetalis has a 25% chance of having Hb Bart hydrops fetalis syndrome, a 50% chance of having αº-thalassemia (α-thalassemia trait), and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her having αº-thalassemia (α-thalassemia trait) is 2/3.

Offspring of a proband. The Hb Bart hydrops fetalis syndrome is usually not compatible with postnatal life.

Other family members of a proband

  • Each sib of the proband’s parents is at a 50% risk of being a carrier of two α-globin gene deletions (αº-thalassemia or α-thalassemia trait).
  • Individuals with α-thalassemia trait typically have mild hypochromia (low MCH), microcytosis (low MCV), anemia, and normal HbA2 and HbF.

Risk to Family Members — Hemoglobin H (HbH) Disease

Parents of a proband

  • The parents of a child with HbH disease usually have different types of αº-thalassemia (α-thalassemia trait) and α+-thalassemia (α-thalassemia silent carrier) mutations:
    • Most commonly, one parent has αº-thalassemia and the other parent has α+-thalassemia. Rarely, one parent has αº-thalassemia and the other parent has α+-thalassemia resulting from a non-deletion mutation.
    • Alternatively, though less likely, one parent is an α°-thalassemia carrier and the other is homozygous for α+-thalassemia. These parents have a 50% chance of having offspring with HbH disease and 50% of having offspring with α+-thalassemia.
    • Uncommonly, both parents carry a specific HBA2 non-deletion α-thalassemia mutationTSaudi, -αIN: 2 bp del) or an initiation codon mutation (HBA2:c.2T>C).
  • Individuals with αº-thalassemia typically have mild microcytosis and normal HbA2 and HbF.
  • Individuals with α+-thalassemia are either hematologically normal or have a mild reduction of MCV and MCH.

Sibs of a proband

  • At conception, each sib of an individual with HbH disease has a 25% chance of having HbH disease, a 25% chance of having αº-thalassemia (α-thalassemia trait), a 25% chance of having α+-thalassemia (α-thalassemia silent carrier), and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her having either αº-thalassemia or α+-thalassemia is 2/3.

Offspring of a proband

  • Each child of an individual with HbH disease inherits the mutation for either αº-thalassemia (α-thalassemia trait) or α+-thalassemia (α-thalassemia silent carrier) and is thus an obligate heterozygote.
  • Given the high carrier rate of αº-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with αº-thalassemia.

Other family members of a proband with either Hb Bart hydrops fetalis or HbH disease. Each sib of the proband's parents is at risk of having α+-thalassemia (α-thalassemia silent carrier) and/or αº-thalassemia (α-thalassemia trait), depending on the genetic status of the relative.

Carrier Detection

Individuals who should be considered for carrier testing:

  • Family members
  • Members of ethnic groups at risk (see Prevalence)
  • Gamete donors for assisted reproductive technologies (ART)

Alphaº-thalassemia carriers (α-thalassemia trait carriers) have a moderate, thalassemia-like hematologic picture. Red blood cell indices show microcytosis (low MCV) and a reduced content of Hb per red cell (low MCH); blood film prepared following incubation of red cells with vital stain displays inclusion bodies in 1:1000 to 1:10,000 red blood cells. Quantitative Hb analysis shows normal percentage of HbA2 and HbF. Identification relies on molecular genetic testing of the α-globin genes, HBA1 and HBA2 (See Table 1 and Table 2). After brilliant cresyl blue (BCB) incubation, rare red blood cell inclusion bodies can be detected in αº-thalassemia carriers.

Alpha+-thalassemia carriers (α-thalassemia silent carriers) may have normal hematologic findings or may have a moderate, thalassemia-like hematologic picture similar to that of a carrier of αº-thalassemia. Identification relies on molecular genetic testing of the α-globin genes, HBA1 and HBA2.

Population Screening

Alphaº-thalassemia. Because of the high carrier rate for αº-thalassemia in certain populations and the availability of genetic counseling and prenatal diagnosis, it is ideal to screen (prior to or early in pregnancy) couples who are members of at-risk populations for αº-thalassemia carrier status to identify those at risk of conceiving a fetus with Hb Bart hydrops fetalis syndrome:

  • If both members of a couple are carriers of an αº-thalassemia deletion mutation (e.g., genotype αα/--SEA), each of their offspring has a 1/4 risk of having Hb Bart hydrops fetalis syndrome.
  • If both members of the couple are carriers of the αº-thalassemia deletion mutation in which both HBA1 and HBA2 as well as HBZ are deleted (i.e., genotype αα/--FIL or genotype of αα/--THAI), they are not at risk of having offspring with Hb Bart hydrops fetalis syndrome because homozygotes for such mutations are lost shortly after conception.
  • If both members of the couple are carriers of a deletion involving both HBA1 and HBA2, but only one of them has a deletion that extends into HBZ (e.g., a couple with genotypes αα/--SEA and αα/--FIL), the couple is at risk of having offspring with Hb Bart hydrops fetalis syndrome because the single HBZ in the fetus produces sufficient ζ-globin for fetal development [Chui & Waye 1998].

Alpha+-thalassemia. Prospective identification of carriers of α+-thalassemia is not strongly indicated, as the offspring of these carriers are not at risk for Hb Bart hydrops fetalis syndrome.

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.

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 have HbH disease, 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. Prenatal testing is possible for couples confirmed by DNA analysis to be at risk of having a fetus with Hb Bart hydrops fetalis syndrome because both parents are carriers of deletion αº-thalassemia. Molecular genetic testing can be performed either on fetal DNA extracted from cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks’ gestation) or by amniocentesis (usually performed at ~15-18 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.

Ultrasound examination. Ultrasonography can also be useful in the management of pregnancies at risk for Hb Bart hydrops fetalis syndrome. In the first trimester, increased nuchal thickness, particularly in an at-risk pregnancy, should prompt appropriate evaluation.

Indeterminate-risk pregnancies. An indeterminate-risk pregnancy is a pregnancy in which EITHER

  • One parent is an αº-thalassemia carrier and the other has an α-thalassemia-like hematologic picture but no αº-thalassemia mutation identified by molecular genetic testing;
    OR
  • The mother is a known αº-thalassemia carrier and the father is unknown or unavailable for testing. This is of concern if the father belongs to a population with a high carrier rate for αº-thalassemia.

In both cases, the options for prenatal testing should be discussed in the context of formal genetic counseling. In such cases, the strategy is fetal DNA analysis for the known αº-thalassemia mutation; if the known αº-thalassemia mutation is present, globin chain synthesis analysis is performed using a fetal blood sample obtained by percutaneous umbilical blood sampling (PUBS) at about 18 to 21 weeks' gestation.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

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@cooleysanemia.org
  • 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

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. Alpha-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 Alpha-Thalassemia (View All in OMIM)

141800HEMOGLOBIN--ALPHA LOCUS 1; HBA1
141850HEMOGLOBIN--ALPHA LOCUS 2; HBA2
142310HEMOGLOBIN--ZETA LOCUS; HBZ
604131ALPHA-THALASSEMIA

Molecular Genetic Pathogenesis

HBA1, HBA2, and HBZ

Alpha-globin genes are duplicated (HBA1 and HBA2) and lie in the telomeric region of chromosome 16 (16p13.3) within a cluster that also contains an embryonic α-like gene (HBZ) and three pseudogenes (HBZP (ψ-ζ), HBAP1 (ψ-α1), HBM (ψ-α2). A θ gene (HBQ1) with an unknown function is located at the 5' end of the cluster (See Figure 1).

HBA1 and HBA2 are embedded within two markedly homologous regions that extend for approximately 4 kb. Their sequence homology is maintained by gene conversion and unequal crossover events. In this DNA region, three highly homologous segments, named X, Y, and Z, separated by non-homologous segments, have been defined (Figure 1).

As a result of unequal genetic exchange, individuals who are phenotypically normal may have four, five, or six α-globin genes and two to six HBZ-like genes. HBA-like globin genes are arranged in the cluster in the order in which they are expressed during development. The genes encoding the α1-globin chain (HBA1) and the α2-globin chain (HBA2) display a marked homology resulting from repeated rounds of gene conversion.

The level of transcription of the two genes differs, as HBA2 produces two to three times more α-globin than HBA1. Regarding the translation profile of HBA1 mRNA and HBA2 mRNA, contrasting results in which percentages of HBA2 mRNA are higher or only slightly higher than percentages of HBA1 mRNA have been reported. The different expression of the two α-globin genes has important clinical implications for the amount of structural α-variant resulting from mutation of HBA1 or HBA2, and for the pathophysiology of the deletion and non-deletion pathologic variants of HBA1 and HBA2.

The expression of HBA1 and HBA2 is regulated by a region (HS-40) located 40 kb upstream from the α-globin cluster (Figure 1). This region contains multiple binding sites for transcriptional factors (NF-E2, GATA-1). The deletion of HS-40 results in an α-thalassemia phenotype, in spite of the structural integrity of both α-globin genes.

Gene structure. Both HBA1 and HBA2 have three coding exons. The mRNAs produced by HBA1 and HBA2 have identical coding regions and can be distinguished only by their 3' UTR. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 4. Deletion HBA1 and/or HBA2 is the most common cause of α-thalassemia:

  • Alpha+-thalassemia. Reciprocal recombination between the Z boxes, which are 3.7 kb apart, or between the X boxes, 4.2 kb apart, gives rise to chromosomes with a single α-globin gene. The two resulting α-thalassemia mutations are referred to respectively as the 3.7-kb rightward deletion (-α3.7) and the 4.2-kb leftward deletion (-α4.2) (Figure 1):
    • In relation to the location of the crossover within the Z box, the -α3.7 deletion is subdivided into three varieties named I, II, and III.
    • In addition to the -α3.7 and the -α4.2 common alleles, other rare deletions involving a single α-globin gene have been reported.
    • These recombinational events also result in the production of chromosomes containing three α-globin genes. A triplicated α-globin gene inherited with heterozygous β-thalassemia results in a mild thalassemia intermedia phenotype.
  • Alphaº-thalassemia. Extended deletions varying from 100 kb to more than 250 kb and removing both α-globin genes (HBA1 and HBA2) (and sometimes the embryonic HBZ gene) result in the complete absence of α-chain production from that allele. Most such deletions are founder mutations that arose by one of several molecular mechanisms, including illegitimate recombination, reciprocal translocation, and truncation of chromosome 16. More than 20 different αº-thalassemia deletions have been reported to date:
    • The most common alleles are the Southeast Asian (--SEA) and the Filipino (--FIL) types.
    • Two deletion alleles, -α5.2 and -α20.5, which remove HBA2 and part of HBA1, produce αº-thalassemia [Higgs 2001].
    • A deletion removing HBA1 and the theta gene (HBQ1) and extending downstream centromeric from the α-globin gene cluster results in αº-thalassemia. The silencing of intact HBA2 in this chromosome is related to an antisense RNA transcribed from the widely expressed LUC7L, becoming juxtaposed to the normal HBA2 by the deletion, and running through the HBA2 sequences [Tufarelli et al 2003].
    • Nine deletions of the HS-40 region also result in the silencing of the intact α-globin genes, thereby producing αº-thalassemia [Higgs 2001].

Non-deletion α-thalassemia. Less frequently, α-thalassemia results from single point mutations or oligonucleotide insertion/deletion in regions critical for α-globin gene expression. In non-deletion α-thalassemia, the affected gene is denoted T (e.g., αTSaudi). Considered as a group, the non-deletion α-thalassemia mutations appear to have a more severe effect on α-globin gene expression and hematologic phenotype than single α-globin gene deletions. This phenomenon may be explained by the majority of the mutations affecting HBA2, whose expression may predominate over HBA1 [Higgs 2001]. No compensatory increase in expression in the remaining functional α gene occurs when the other is inactivated by a point mutation, in contrast to the compensatory increase in expression in the remaining functional α gene when a single α-globin gene is deleted (e.g., the -α3.7 deletion).

At present, more than 70 well-defined causes of non-deletion α-thalassemia are listed in the public HGMD (www.hgmd.org).

The molecular mechanisms leading to the silencing of either HBA1 or HBA2 include: mutations involving RNA splicing, the poly (A) additional signal, the initiation of mRNA translation, as well as missense mutation of the termination, in-frame deletions, frame-shift mutations, and nonsense mutations. Mutations of α-globin genes that result in the production of hyper-unstable globin variants such as HbQuong Sze and that are unable to assemble into stable β4 tetramers and are thus rapidly degraded, may also result in α-thalassemia (Table 1) [Higgs 2001].

The most common non-deletion mutation, which is frequently seen in Southeast Asia, is HbConstant Spring (HbCS), resulting from a mutation of the stop codon of HBA2. This mutation leads to the production of an α-globin chain elongated by 31 amino acids. HbCS is produced in very small amounts because its mRNA is unstable. Heterozygotes for HbCS and other rare elongated variants, along with the presence of the Hb variant, produce the αº-thalassemia phenotype.

Some of the mutations causing α-chain structural variants may occur in a chromosome with only one α-globin gene (e.g., HbQThailand, HbGPhiladelphia). (For more information, see Table A.)

Table 4. Selected HBA1 and HBA2 Pathogenic Variants

DNA Nucleotide Change 1
(Standard Nomenclature 2
Protein Amino-Acid Change 1 or Functional Globin Genes Deleted 3
(Standard Nomenclature 2)
Reference Sequences
(HBA2:c.2T>C)Alpha2 initiation codon Met>Thr; -α NcoI of HBA2
(HBA2:p.Met1Thr)
NM_000517​.4
NP_000508​.1
(HBA2:c.377T>C)Alpha2 Leu125Pro,
Hb Quong Sze
(HBA2:p.Leu126Pro)
(HBA2:c.427T>C)Alpha2 142, Stop>Gln
HbConstant Spring (HbCS)
(HBA2:p.Ter143Glnext32)
Codon 30/31 2-bp deletion
(HBA2:c.94_95delAG)
The deletion of 2 nucleotides causes a frameshift & premature termination at codon(TAA)
(HBA2:p.Arg32AspfsTer24)
HBA2:c.[339C>G; 340_351delCTCCCCGCCGAG]Alpha2 His112Gln and deletion of codons 113-116 -
Leu-Pro-Ala-Glu,
Hb Lleida
(HBA2:p.His113Gln; p.Leu114_Glu117del)
NM_000517​.4
NP_000508​.1
Splicing sites -αHphI α, HphI digestion for the pentanucleotide HBA2 IVS-1 deletion
(HBA2:c.95+2_95+6delTGAGG)
--
HBA1:c.223G>CAsp74Gly, HbQ-Thailand
(HBA1:p.Asp75Gly)
NM_000558​.3
NP_000549​.1
HBA2:c.[207C>G (or HBA1) or 207C>A]Asn68Lys, HbG Philadelphia
(HBA2 or HBA1: p:Asn69Lys)
NM_000517​.4
NP_000508​.1
PolyA addition site of HBA2
(AATAAA >AATAAG)
(HBA2:c.*+94A>G)
Alpha2 αTSaudi
-α IN: 2 bp del
(c.[-2_-3delAC; -α3.74)
Deletion of HBA2 and of nucleotides that additionally impair translation
3.7Deletion of HBA2Z84721​.1
4.2Deletion of HBA2
5.2 Deletion of HBA2 and 5’ end of HBA1 5
20.5
(g.15164_37864del22701) 6
Deletion of HBA2 and 5’ end of HBA1
 −−FIL
(g.11684_43534del31851) 6
Deletion of HBA2 and HBA1
 −−MED
(g.24664_41064del16401) 6
Deletion of HBA2 and HBA1
 −−SEA
(g.26264_45564del19301) 6
Deletion of HBA2 and HBA1
 −−THAI
(g.10664_44164del33501) 6
Deletion of HBA2 and HBA1

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. Globin mutations are given by their conventional nomenclature (globin​.cse.psu.edu/)

2. Standard naming conventions of the Human Genome Variation Society (www​.hgvs.org), as listed by the Globin Gene Server

3. Only functional globin genes involved in the deletion are given; deleted pseudogenes are not listed.

4. Denotes two variations in one allele: deletion of AC at -2 and -3 before ATG initiation codon in cis configuration on an -α3.7 deletion allele [Viprakasit et al 2003]

5. Pressley et al [1980]

6. Coordinates from entries in the Globin Gene Server; it is not known if all deletions in these categories will have precisely the same nucleotide coordinates.

Normal gene product. The α-globin chains produced by HBA1 and HBA2 mRNAs have identical amino acid sequences. The heterodimer protein hemoglobin A is made up of two α chains and two β chains.

Abnormal gene product. The consequence of a single α-globin gene deletion is reduced production of α-globin chains by the affected chromosome+-thalassemia). Measurement of α-globin mRNA indicates that the -α4.2 mutation is not associated with a compensatory increase in expression in the remaining HBA1, whereas with the -α3.7 mutation, the remaining HBA1 expression is roughly halfway between that of normal HBA2 and HBA1 (Figure 1).

References

Published Guidelines/Consensus Statements

  1. ACOG Committee on Obstetrics; ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy. Obstet Gynecol. 2007;109:229–37. [PubMed: 17197616]
  2. Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. Available online. 2009. Accessed 6-17-14. [PubMed: 20008179]

Literature Cited

  1. Bernini LF. Geographic distribution of alpha thalassemia. In: Steinberg MH, Forget PG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge, UK: Cambridge University Press; 2001:878-94.
  2. Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003;101:791–800. [PubMed: 12393486]
  3. Chui DH, Waye JS. Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood. 1998;91:2213–22. [PubMed: 9516118]
  4. De Gobbi M, Viprakasit V, Hughes JR, Fisher C, Buckle VJ, Ayyub H, Gibbons RJ, Vernimmen D, Yoshinaga Y, de Jong P, Cheng JF, Rubin EM, Wood WG, Bowden D, Higgs DR. A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science. 2006;312:1215–7. [PubMed: 16728641]
  5. Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. Hematology Am Soc Hematol Educ Program. 2009:26–34. [PubMed: 20008179]
  6. Galanello R, Aru B, Dessi C, Addis M, Paglietti E, Melis MA, Cocco S, Massa P, Giagu N, Barella S. et al. HbH disease in Sardinia: molecular, hematological and clinical aspects. Acta Haematol. 1992;88:1–6. [PubMed: 1414154]
  7. Gibbons RJ, Pellagatti A, Garrick D, Wood WG, Malik N, Ayyub H, Langford C, Boultwood J, Wainscoat JS, Higgs DR. Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS). Nat Genet. 2003;34:446–9. [PubMed: 12858175]
  8. Gibson WT, Harvard C, Qiao Y, Somerville MJ, Lewis ME, Rajcan-Separovic E. Phenotype-genotype characterization of alpha-thalassemia mental retardation syndrome due to isolated monosomy of 16p13.3. Am J Med Genet A. 2008;146A:225–32. [PubMed: 18076105]
  9. Harteveld CL, Kriek M, Bijlsma EK, Erjavec Z, Balak D, Phylipsen M, Voskamp A, Capua E, White SJ, Giordano PC. Refinement of the genetic cause of ATR-16. Hum Genet. 2007;122:283–92. [PubMed: 17598130]
  10. Higgs DR, Bowden DK. Clinical and laboratory features of the alpha-thalassemia syndromes. In: Steinberg MH, Forget PG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge, UK: Cambridge University Press; 2001:431-69.
  11. Higgs DR. Gene regulation in hematopoiesis: new lessons from thalassemia. Hematology Am Soc Hematol Educ Program. 2004:1–13. [PubMed: 15561673]
  12. Higgs DR. Molecular mechanisms of alpha thalassemia. In: Steinberg MH, Forget PG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge, UK: Cambridge University Press; 2001:405-30.
  13. Lindor NM, Valdes MG, Wick M, Thibodeau SN, Jalal S. De novo 16p deletion: ATR-16 syndrome. Am J Med Genet. 1997;72:451–4. [PubMed: 9375730]
  14. Lorey F, Charoenkwan P, Witkowska HE, Lafferty J, Patterson M, Eng B, Waye JS, Finklestein JZ, Chui DH. Hb H hydrops foetalis syndrome: a case report and review of literature. Br J Haematol. 2001;115:72–8. [PubMed: 11722414]
  15. Musallam KM, Cappellini MD, Wood JC, Taher AT. Iron overload in non-transfusion-dependent thalassemia: a clinical perspective. Blood Rev. 2012;26 Suppl 1:S16–9. [PubMed: 22631036]
  16. Origa R, Sollaino MC, Giagu N, Barella S, Campus S. Clinical and molecular analysis of haemoglobin H disease in Sardinia: hematological, obstetric and cardiac aspects in patients with different genotypes. Br J Haematol. 2007;136:326–32. [PubMed: 17129226]
  17. Picketts DJ, Tastan AO, Higgs DR, Gibbons RJ. Comparison of the human and murine ATRX gene identifies highly conserved, functionally important domains. Mamm Genome. 1998;9:400–3. [PubMed: 9545503]
  18. Pressley L, Higgs DR, Aldridge B, Metaxatou-Mavromati A, Clegg JB, Weatherall DJ. Characterisation of a new alpha thalassemia 1 defect due to a partial deletion of the alpha globin gene complex. Nucleic Acids Res. 1980;8:4889–98. [PMC free article: PMC324266] [PubMed: 6255436]
  19. Steensma DP, Gibbons RJ, Higgs DR. Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. Blood. 2005;105:443–52. [PubMed: 15358626]
  20. Steensma DP, Higgs DR, Fisher CA, Gibbons RJ. Acquired somatic ATRX mutations in myelodysplastic syndrome associated with alpha thalassemia (ATMDS) convey a more severe hematologic phenotype than germline ATRX mutations. Blood. 2004a;103:2019–26. [PubMed: 14592816]
  21. Steensma DP, Viprakasit V, Hendrick A, Goff DK, Leach J, Gibbons RJ, Higgs DR. Deletion of the alpha-globin gene cluster as a cause of acquired alpha-thalassemia in myelodysplastic syndrome. Blood. 2004b;103:1518–20. [PubMed: 14576055]
  22. Taher AT, Porter J, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, Siritanaratkul N, Galanello R, Karakas Z, Lawniczek T, Ros J, Zhang Y, Habr D, Cappellini MD. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012;120:970–7. [PubMed: 22589472]
  23. Traeger-Synodinos J, Papassotiriou I, Metaxotou-Mavrommati A, Vrettou C, Stamoulakatou A, Kanavakis E. Distinct phenotypic expression associated with a new hyperunstable alpha globin variant (Hb Heraklion, alpha1cd37 (C2)Pro>0): comparison to other alpha-thalassemic hemoglobinopathies. Blood Cells Mol Dis. 2000;26:276–84. [PubMed: 11042028]
  24. Tufarelli C, Stanley JA, Garrick D, Sharpe JA, Ayyub H, Wood WG, Higgs DR. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet. 2003;34:157–65. [PubMed: 12730694]
  25. Vaeusorn O, Fucharoen S, Ruangpiroj T, et al. Fetal pathology and maternal morbidity in hemoglobin Bart's hydrops fetalis: An analysis of 65 cases. Bangkok, Thailand: First International Conference on Thalassemia; 1985.
  26. Vichinsky EP. Alpha thalassemia major--new mutations, intrauterine management, and outcomes. Hematology Am Soc Hematol Educ Program. 2009:35–41. [PubMed: 20008180]
  27. Viprakasit V, Ayyub H, May A. Dinucleotide deletion in -alpha3.7 allele causes a severe form of alpha+ thalassemia. Eur J Haematol. 2003;71:133–6. [PubMed: 12890155]

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 (2005-2012)
Renzo Galanello, MD; Ospedale Regionale Microcitemie (2005-2013)
Paolo Moi, MD (2013-present)
Raffaella Origa, MD (2013-present)

Revision History

  • 21 November 2013 (me) Comprehensive update posted live
  • 7 June 2011 (me) Comprehensive update posted live
  • 14 July 2008 (me) Comprehensive update posted live
  • 1 November 2005 (me) Review posted to live Web site
  • 3 January 2005 (rg) Original submission
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