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Alpha-Thalassemia

, MD and , MD.

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Initial Posting: ; Last Update: December 29, 2016.

Summary

Clinical characteristics.

Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome, caused by deletion of all four α-globin genes; and hemoglobin H (HbH) disease, most frequently caused by deletion of three α-globin genes.

  • 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. Additional clinical features include marked hepatosplenomegaly, extramedullary erythropoiesis, hydrocephalus, and cardiac and urogenital defects. Death usually occurs in the neonatal period.
  • HbH disease is characterized by microcytic hypochromic hemolytic anemia, splenomegaly, mild jaundice, and sometimes thalassemia-like bone changes. Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to oxidant drugs and infections.

Diagnosis/testing.

The diagnosis of Hb Bart syndrome is established in a fetus with the characteristic radiographic and laboratory features. Identification of biallelic pathogenic variants in HBA1 and HBA2 that result in deletion or inactivation of all four α-globin alleles confirms the diagnosis. The diagnosis of HbH disease is established in a proband with the characteristic laboratory and clinical features. Identification of biallelic pathogenic variants in HBA1 and HBA2 that result in deletion or inactivation of three α-globin alleles confirms the diagnosis.

Management.

Treatment of manifestations: Intrauterine blood transfusions, improved transfusion strategies, and rarely curative hematopoietic stem cell transplant may allow survival of children with Hb Bart syndrome. 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: Because of the severity of Hb Bart syndrome and the risk for maternal complications, prenatal diagnosis and early termination of pregnancies at risk has usually been considered. However, recent advances in intrauterine and postnatal therapy have increased treatment options – thus complicating the ethical issues for health care providers and families facing an affected pregnancy.

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: For HbH disease, 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: Complications reported in pregnant women with HbH disease include 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 α-thalassemia trait with a two-gene deletion or inactivation in cis (--/αα), and a 25% chance of being unaffected and not a carrier.

At conception, if one parent has α-thalassemia trait with a two-gene deletion in cis (--/αα) and the other parent is an α-thalassemia silent carrier (1-gene deletion; -α/αα), each sib of an individual with HbH disease has a 25% chance of having HbH disease, a 25% chance of having α-thalassemia trait, a 25% chance of being an α-thalassemia silent carrier, and a 25% chance of being unaffected and not a carrier. Each child of an individual with HbH disease inherits either the two-gene deletion in cis and has α-thalassemia trait or is an α-thalassemia silent carrier and is thus an obligate heterozygote; risk to the child of having the 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 α-thalassemia trait with a two-gene deletion in cis (--/αα) can be identified prior to pregnancy as being 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 α-thalassemia carrier with a two-gene deletion in cis (--/αα) when the other parent is either unknown or unavailable for testing.

GeneReview Scope

Alpha-Thalassemia (α-Thalassemia)
Phenotype 1Genotype
Hemoglobin Bart hydrops fetalis (Hb Bart) syndromeLoss of all 4 α-globin genes
Hemoglobin H (HbH) diseaseLoss of 3 α-globin genes
α-thalassemia traitLoss of 2 α-globin genes either in cis (--/αα, α0 carrier) or in trans (-α/-α)
α-thalassemia silent carrierLoss of 1 α-globin gene (-α/αα, α+ carrier)

For synonyms and outdated names see Nomenclature.

1.

In descending order of severity

Diagnosis

Suggestive Findings

Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis syndrome (deletion of all 4 α-globin genes; --/--), and hemoglobin H disease (most frequently caused by deletion of 3 α-globin genes; --/-α).

Hemoglobin Bart Hydrops Fetalis Syndrome

Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome should be suspected in fetuses with the following ultrasonographic features and/or laboratory features.

Radiographic features

  • An at-risk fetus with increased nuchal thickness, thickened placenta, increased cerebral media artery velocity, and increased cardiothoracic ratio on ultrasonography examination at 13 to 14 weeks' gestation
  • A fetus with generalized edema, ascites, and pleural and pericardial effusions detected by ultrasonography examination at 22 to 28 weeks' gestation

Laboratory features

  • Red blood cell indices: severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (see Table 1)
  • Reticulocytosis: variable; may be more than 60%
  • Peripheral blood smear with large, hypochromic red cells and severe anisopoikilocytosis

Hemoglobin H Disease

Hemoglobin H (HbH) disease should be suspected in an infant or child with the following newborn screening results, clinical features, and/or laboratory features.

Newborn screening. Hb Bart >15% at birth

Note: (1) 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). (2) Reference ranges may very among laboratories performing newborn screening (3) Low concentrations of Hb Bart (1%-8%) are indicative of the carrier states and usually do not need further evaluation.

Clinical features

  • Hepatosplenomegaly
  • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences)
  • Mild jaundice

Laboratory features

  • Red blood cell indices: mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (see Table 1)
  • Moderate reticulocytosis: 3%-6%
  • Peripheral blood smear with anisopoikilocytosis, and very rare nucleated red blood cells (i.e., erythroblasts)
  • Red blood cell supravital stain showing HbH inclusions (β4 tetramers) in 5% to 80% of erythrocytes following incubation of fresh blood smears with 1% brilliant cresyl blue for one to three hours

Table 1.

Red Blood Cell Indices in Individuals with Hemoglobin Bart Hydrops Fetalis and Hemoglobin H Disease

Red Blood Cell IndicesNormalAffected
MaleFemaleHemoglobin Bart hydrops fetalis 1Hemoglobin H disease 2
Mean corpuscular volume (MCV, fl)89.1±5.0187.6±5.5136±5.1Children: 56±5
Adults: 61±4
Mean corpuscular hemoglobin (MCH, pg)30.9±1.930.2±2.131.9±918.4±1.2
Hemoglobin (Hb, g/dL)15.9±1.014.0±0.93-8Male: 10.9±1.0
Female: 9.5±0.8

Hemoglobin Analysis

Qualitative and quantitative hemoglobin (Hb) 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. The Hb pattern in α-thalassemia varies by α-thalassemia type (see Table 2). The Hb types most relevant to α-thalassemia are:

  • Hemoglobin A (HbA). Two α-globin chains and two β-globin chains (α2β2)
  • Hemoglobin F (HbF). Two α-globin chains and two γ-globin chains (α2γ2)
  • Hemoglobin Bart (Hb Bart). Four γ-globin chains (γ4)
  • Hemoglobin H (HbH). Four β-globin chains (β4)
  • Hemoglobin A2 (HbA2). Two α-globin chains and two δ-globin chains (α2δ2)
  • Hemoglobin Portland. Two ζ-globin chains and two γ-globin chains (ζ2γ2)

Table 2.

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

Hemoglobin TypeNormalAffected
Hb Bart hydrops fetalis syndrome 1HbH disease 2
HbA96%-98%060%-90%
HbF<1%0<1.0%
Hb Bart085%-90%2%-5%
HbH000.8%-40%
HbA22%-3%0<2.0%
Hb Portland010%-15%0
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

See Genetic Counseling for information about hematologic testing to identify alpha-thalassemia trait and alpha-thalassemia silent carrier status.

Establishing the Diagnosis

The diagnosis of hemoglobin Bart hydrops fetalis syndrome is established in a fetus with the above ultrasonographic and laboratory features. Identification of biallelic pathogenic variants in both HBA1 and HBA2 that results in deletion or inactivation of all four α-globin alleles (e.g., 2 α-globin deletions in the homozygous state; --/--) on molecular genetic testing (see Table 1) confirms the diagnosis and allows for family studies.

The diagnosis of hemoglobin H disease is established in a proband with the above clinical and laboratory features. Identification of pathogenic variants in HBA1 and HBA2 on molecular genetic testing (see Table 1) that results in deletion or inactivation of three α-globin genes (e.g., a 2 α-globin-deletion allele in trans with a single α-globin-deletion allele; --/-α3.7) confirms the diagnosis and allows for family studies.

See Figure 1 for a diagnostic algorithm for hemoglobinopathies.

Figure 1.

Figure 1.

Diagnostic algorithm for hemoglobinopathies

Molecular testing approaches can include targeted deletion analysis for common deletions, sequence analysis, and deletion analysis of HBA1, HBA2 and the HS-40 regulatory region.

Targeted deletion analysis for common deletions of HBA1and HBA2 can be performed first.

  • Common two α-globin-gene deletions (αº-genotype)
    Note: (1) These common deletions are typically founder variants (see Prevalence). (2) More than 20 different deletions ranging from ~6 kb to >300 kb and removing both α-globin genes (and sometimes embryonic HBZ) have been reported.
  • Common single α-globin-gene deletions (α+-genotype)
    Note: In addition to these two common deletions, rare deletions involving a single α-globin gene have been reported.

Sequence analysis of HBA1 and HBA2 can be performed next if a common deletion was not identified.

Note: Non-deletion or “trait” HBA2 variants are designated as (αNDα/) or (αTα/); variants in HBA1 are designated as (ααND /) or (ααT /) (see Molecular Genetics).

Deletion analysis of HBA1, HBA2, and the HS-40 regulatory region located 40 kb upstream from the α-globin cluster can be performed next to detect uncommon deletions associated with α-thalassemia if pathogenic variants have not been identified by targeted deletion testing or sequence analysis.

Further testing for genes associated with genetic disorders similar to α-thalassemia, such as ATRX and HBB (see Differential Diagnosis) may also be considered if clinically indicated.

Table 3.

Molecular Genetic Testing Used in Alpha-Thalassemia

Genes 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method 3
HBA1 and HBA2Targeted common deletion analysis 4~85%
Sequence analysis 5, 6~15%
Deletion analysis 7≤5%
1.
2.

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

3.
4.

Targeted deletion assays can detect specific deletions within the α-globin gene cluster. The method commonly used to identify targeted deletion is GAP-PCR.

5.

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

6.

Targeted analysis for known pathogenic variants (genotyping) may also be used. Methods used may include: allele-specific PCR, allele-specific oligonucleotide testing, and restriction fragment length polymorphism (RFLP) testing.

7.

Methods that may be used to detect rare or unknown deletions include: Southern blotting, quantitative PCR, long-range PCR and MPLA. The same methods may be used to detect duplications of the α-cluster. Deletion analysis should include the HS-40 regulatory region located 40 kb upstream from the α-globin cluster.

Clinical Characteristics

Clinical Description

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 delivered stillborn at 30 to 40 weeks’ gestation or die soon after birth.

The main clinical features are generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia. Notably, red cells with Hb Bart have an extremely high oxygen affinity and are incapable of effective oxygen delivery. The blood smear shows large hypochromic macrocytes and numerous nucleated red cells. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common.

Retardation in brain growth, hydrocephalus, cardiovascular deformities, and urogenital defects have been reported.

A very small number of individuals survive following intrauterine transfusions and repeated frequent transfusions after birth.

Maternal complications during pregnancy commonly include: preeclampsia, polyhydramnios or oligohydramnios, antepartum hemorrhage, and premature delivery.

HbH disease. The phenotype of HbH disease varies. Although clinical features usually develop in the first years of life, HbH disease may not present until adulthood or may be diagnosed only during routine hematologic analysis in an asymptomatic individual.

The majority of individuals show microcytic hypochromic hemolytic anemia (see Table 1), enlargement of the spleen and less commonly of the liver, mild jaundice, and sometimes mild-to-moderate thalassemia-like skeletal changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) that affects the facial features. Leg ulcers are rare.

Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to oxidant drugs and infections. Rarely, aplastic crisis due to infection of parvovirus B19 may occur in individuals with HbH disease.

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].

Significant iron overload is uncommon but has been reported in older individuals, usually as a result of repeated blood transfusions or increased iron absorption [Taher et al 2012].

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 α-thalassemia pathogenic variants, α-globin mRNA levels, α-globin synthesis, and clinical manifestations of α-thalassemia is well documented.

Hb Bart syndrome

  • Most often caused by large deletions on both alleles (α-globin --/--)
  • Rarely, an individual with Hb Bart syndrome will have a non-deletion variant.

HbH disease

Alpha-thalassemia trait

  • May result from deletion or inactivation of two α-globin genes in cis (--/αα)
  • May result from deletion of a single gene on both alleles (e.g., -α3.7/-α3.7)
  • May result from non-deletion variants inactivating HBA2NDα/αα)
    Individuals with alpha-thalassemia trait with a two-gene deletion in cis (--/αα) have slightly lower RBC indices than individuals with a two-gene deletion in trans. The most severe alleles in descending order are: two-gene deletion in cis, non-deletion HBA2 variant, -α4.2, -α3.7 (because of compensatory increase of α-globin production from the remaining HBA1), and non-deletion HBA1 variant. For the -α4.2 deletion, evidence is inconclusive for a compensatory increase in the expression of the remaining α-globin gene.
  • The phenotype may be modified by triplication or quadruplication of the α-globin genes on one chromosome.

Alpha-thalassemia silent carrier

  • Results from deletion of one α-globin gene (-α/αα) or inactivation of HBA1 (ααND/αα)
  • The genotypes causing silent alpha-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 individuals with α-thalassemia trait.

Nomenclature

The α-thalassemias have been classified on the basis of the total globin production from each of the two α-globin genes, HBA1 and HBA2, present on chromosome 16:

  • When both α-globin genes on a chromosome are deleted or inactivated, the allele is referred to as α0 (no output of α-globin from the chromosome). An individual with the genotype --/αα is referred to as an α0 carrier.
  • When one α-globin gene on a chromosome is deleted or inactivated by a non-deletion variant the allele is called α+ (some α-globin is produced). An individual with the genotype -α/αα is referred to as an α+ carrier.

Alpha-thalassemias have also been classified based on the number of globin genes that are missing or abnormal: alpha-thalassemia 1 (-α/αα, α-thalassemia silent carrier); alpha-thalassemia 2 (-α/-α or --/αα, α-thalassemia trait) [Lehmann & Carrell 1984].

Prevalence

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

More precise data have been obtained using molecular testing. For detailed references for the frequency of α-thalassemia in each population, see Piel & Weatherall [2014].

Africa

The highest allele frequency (0.30-0.40) of the -α3.7allele has been observed in the equatorial belt including Nigeria, Ivory Coast, and Kenya.

The two α-globin-gene deletion in cis (--/αα) has been reported very rarely in North Africa and in the African American population.

The Mediterranean

Alpha-thalassemia trait caused by -α3.7/-α3.7 is common, with the highest allele frequency reported in Sardinia (0.18) and the lowest in Spain.

The two α-globin-gene deletion in cis (--/αα) is very rare (0.002); thus, Hb Bart hydrops fetalis is only rarely reported.

A remarkable aspect of α-thalassemia variants identified in the Mediterranean population is the heterogeneity of variants, particularly the non-deletion variants.

The Arabian Peninsula

Frequency of the -α3.7allele (causing α-thalassemia trait) varies from 0.01 to 0.67, with the highest values being observed in Oman.

The two α-globin-gene deletion in cis (--/αα) is extremely rare.

India

Alpha-thalassemia trait reaches very high allele 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 -α3.7allele and the -α4.2allele variably contribute to incidence of α-thalassemia trait.

The two α-globin-gene deletion in cis (--/αα) is very rare.

Southeast Asia

Alpha0-thalassemia alleles (−−SEA, −−THAI, −−FIL) and α+-thalassemia alleles (-α) are very common, causing a major public health burden.

Alpha-thalassemia caused by HbConstant Spring (HbCS) alleles is also 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 variants have a variant in a regulatory element that creates a GATA-1 site and activates a cryptic promoter [De Gobbi et al 2006].

The two α-globin-gene deletion in cis (--/αα) is very rare.

Differential Diagnosis

Hydrops Fetalis

Hydrops fetalis is associated with many conditions in addition to Hb Bart, including immune-related disorders (e.g., alloimmune hemolytic disease, 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.

Hemoglobin H (HbH) 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 supravital 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 widely spaced eyes, short nose, tented vermilion of the upper lip, and thick or everted vermilion of the 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. ATRX syndrome is caused by mutation of ATRX and inherited in an X-linked manner.

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). In ATRX syndrome, the α-globin gene cluster and the HS-40 regulatory region of chromosome 16 are structurally intact.

Acquired variants in ATRX can arise in myelodysplastic syndrome and cause an acquired form of HbH disease (see Genetically Related Disorders, Acquired α-thalassemia).

Carrier States (αº-Thalassemia and α+-Thalassemia)

Beta-thalassemia. Microcytosis and hypochromia are present in αº-thalassemia carriers, hematologically manifesting α+-thalassemia carriers, and β-thalassemia carriers; β-thalassemia carriers, however, are distinguished by a high percent of HbA2.

Iron deficiency anemia. Alpha-thalassemia trait 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 α0-thalassemia carriers. Though some overlap with α-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.

Management

In 2013, the Thalassemia International Federation published Guidelines for the Management of Non Transfusion-Dependent Thalassemia (NTDT), including beta-thalassemia intermedia, HbH disease and HbE/beta-thalassemia. 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 and Preimplantation Genetic Diagnosis.

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 consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Hb Bart syndrome was previously considered a universally fatal condition, however, its prognosis is shifting because of prenatal diagnosis, intrauterine blood transfusions, improved transfusion strategies, and (rarely) curative hematopoietic stem cell transplant [Pecker et al 2017]. Although the Thalassemia International Guidelines recommend a transfusion strategy similar to β-thalassemia for these individuals; however, no reports on optimal transfusion management exist [Amid et al 2016]. Because few children with Hb Bart syndrome survive, clinical trials to assess these treatment approaches are lacking.

The 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.
  • Iron chelation therapy may be needed in individuals with iron loading caused by regular blood transfusion, inappropriate iron therapy, or abnormal iron absorption.
  • Splenectomy should be performed only in individuals with massive splenomegaly or hypersplenism; the associated risks for severe, life-threatening sepsis and 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 syndrome

Because of the severity of Hb Bart 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. Future studies on the functional outcomes of children with Hb Bart syndrome who have received chronic transfusion, intrauterine transfusions, and hematopoietic stem cell transplant, will allow physicians to improve the informed decision-making process for families weighing the risk-benefit profile of present treatment options.

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 has been shown to be superior to placebo in reducing liver iron concentration in those older than age ten years who have beta-thalassemia intermedia, HbE/beta-thalassemia, and HbH disease [Taher et al 2012].

Regular folic acid supplementation should be recommended, 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 evaluated as soon as possible after birth to determine if they have HbH disease so that appropriate monitoring can be instituted. Evaluations can include:

  • Evaluation of red blood cell indices, red blood cell supravital stain for HbH inclusions and hemoglobin analysis by HPLC
  • Targeted molecular analysis if the pathogenic variants in the family are known
  • Molecular genetic analysis (according to the frequency of α-globin gene pathogenic variants in each geographic area) if the pathogenic variants in the family are not known.

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

Pregnancy Management

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 syndrome have α-thalassemia trait.
  • Individuals with α-thalassemia trait typically have mild hypochromic (low MCH), microcytic (low MCV) anemia, and normal HbA2 and HbF.

Sibs of a proband. At conception, each sib of a proband with Hb Bart syndrome has a 25% chance of having Hb Bart syndrome, a 50% chance of having α-thalassemia trait with a two-gene deletion in cis (--/αα), and a 25% chance of being unaffected and not a carrier.

Offspring of a proband. Hb Bart syndrome is often not compatible with postnatal life.

Other family members of a proband

  • Each sib of the proband’s parents is at a 50% risk of having α-thalassemia trait with a two-gene deletion in cis (--/αα).
  • Individuals with α-thalassemia trait typically have mild hypochromic (low MCH), microcytic (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 genotypes:

  • Most commonly, one parent has α-thalassemia trait with a two-gene deletion in cis (--/αα) and the other parent is an α-thalassemia silent carrier (1-gene deletion; -α/αα). Rarely, one parent has α-thalassemia trait with a two-gene deletion in cis (--/αα) and the other parent is an α-thalassemia carrier with a non-deletion variant.
  • Alternatively, though less likely, one parent has α-thalassemia trait with a two-gene deletion in cis (--/αα) and the other parent has α-thalassemia trait with a two-gene deletion in trans (-α/-α). These parents have a 50% chance of having offspring with HbH disease and a 50% chance of having offspring with one-gene deletion (α-thalassemia silent carrier; -α/αα).
  • Uncommonly, both parents carry a specific HBA2 non-deletion α-thalassemia variant (e.g., αT Saudi, HBA2:c.*93_*94delAA)
  • Individuals with α-thalassemia trait typically have mild microcytosis and normal HbA2 and HbF.
  • Alpha-thalassemia silent carriers (loss of 1 α-globin gene) 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 whose parents have the most common variants (1 parent has --/αα and the other parent has -α/αα) has a 25% chance of having HbH disease, a 25% chance of having α-thalassemia trait with a two-gene deletion in cis (--/αα), a 25% chance of being an α-thalassemia silent carrier with loss of one α-globin gene, and a 25% chance of being unaffected and not a carrier.

Offspring of a proband

  • Each child of an individual with HbH disease inherits a loss of two α-globin genes in cis (α-thalassemia trait) or a loss of one α-globin gene (α-thalassemia silent carrier) and is thus an obligate heterozygote.
  • Given the high carrier rate of α-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with α-thalassemia trait with a loss of two α-globin genes in cis (--/αα).

Other family members of a proband with either Hb Bart syndrome or HbH disease. Each sib of the proband's parents is at risk of having loss of one α-globin gene (α-thalassemia silent carrier) and/or α-thalassemia trait with a loss of two α-globin genes in cis (--/αα).

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)

Alpha-thalassemia trait is associated with a moderate, thalassemia-like hematologic picture (see Table 4). Identification relies on molecular genetic testing of the α-globin genes, HBA1 and HBA2 (see Table 3).

Alpha-thalassemia silent carriers may have normal hematologic findings or may have a moderate, thalassemia-like hematologic picture similar to individuals with α-thalassemia trait (see Table 4). Identification relies on molecular genetic testing of the α-globin genes, HBA1 and HBA2 (see Table 3).

Table 4.

Red Blood Cell Indices in Alpha-Thalassemia Trait and Silent Carrier

Red Blood Cell IndicesNormalCarrier 1
MaleFemaleAlpha-Thalassemia Trait 2
(--/αα or -α/-α)
Alpha-Thalassemia Silent Carrier
(-α/αα)
Mean corpuscular volume (MCV, fl)89.1±5.0187.6±5.571.6±4.181.2±6.9
Mean corpuscular hemoglobin (MCH, pg)30.9±1.930.2±2.122.9±1.326.2±2.3
Hemoglobin (Hb, g/dL)15.9±1.014.0±0.9Male: 13.9±1.7
Female: 12.0±1.0
Male: 14.3±1.4
Female: 12.6±1.2

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

Qualitative and quantitative hemoglobin (Hb) 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 (Table 5).

  • Hemoglobin A (HbA). Two α-globin chains and two β-globin chains (α2β2)
  • Hemoglobin F (HbF). Two α-globin chains and two γ-globin chains (α2γ2)
  • Hemoglobin H (HbH). Four β-globin chains (β4)
  • Hemoglobin A2 (HbA2). Two α-globin chains and two δ-globin chains (α2δ2)
  • Hemoglobin Bart (Hb Bart). Four γ-globin chains (γ4)
  • Hemoglobin Portland. Two ζ-globin chains and two γ-globin chains (ζ2γ2)

Table 5.

Hemoglobin Patterns in Alpha-Thalassemia Trait and Silent Carrier

Hemoglobin TypeNormalAlpha-thalassemia trait 1
(--/αα or -α/-α)
Alpha-thalassemia silent carrier 2
(-α/αα)
HbA96%-98%96%-98%96%-98%
HbF<1%<1.0%<1.0%
HbH000
HbA22%-3%1.5%-3.0%2%-3%
Hb Bart000
Hb Portland000
1.

Deletion or inactivation of two α-globin genes either in cis configuration (--/αα) or in trans configuration (-α/-α)

2.

Deletion or inactivation of one α-globin gene (-α/αα)

Population Screening

Alpha-thalassemia trait with a loss of two α-globin genes in cis (--/αα). Because of the high carrier rate for the two-gene deletion in cis (--/αα) 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 to identify those at risk of conceiving a fetus with Hb Bart syndrome:

If both members of a couple are carriers of an αº-thalassemia deletion variant (e.g., genotype --SEA/αα), all of their offspring have a 1/4 risk of having Hb Bart syndrome.

If both members of the couple are carriers of the αº-thalassemia deletion variant in which both HBA1 and HBA2 as well as HBZ are deleted (i.e., genotypeFIL/αα or genotype –THAI/αα), they are not at risk of having offspring with Hb Bart syndrome because homozygotes for such pathogenic variants 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 –SEA/αα and –FIL/αα), the couple is at risk of having offspring with Hb Bart syndrome because the single HBZ in the fetus produces sufficient ζ-globin for fetal development [Chui & Waye 1998].

Alpha-thalassemia silent carrier. Prospective identification of α-thalassemia silent carriers is not strongly indicated, as the offspring of these carriers are not at risk for Hb Bart 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 and Preimplantation Genetic Diagnosis

High-risk pregnancies. Prenatal testing is possible for couples confirmed by DNA analysis to be at risk of having a fetus with Hb Bart syndrome because both parents are carriers of a two-gene deletion in cis (--/αα). Molecular genetic testing can be performed either on fetal DNA extracted from cells obtained by chorionic villus sampling or by amniocentesis.

Ultrasound examination. Ultrasonography can also be useful in the management of pregnancies at risk for Hb Bart 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 for which ONE of the following is true:

  • One parent has α-thalassemia trait with a loss of two α-globin genes in cis (e.g., --/αα) and the other has an α-thalassemia-like hematologic picture but no α-thalassemia variant identified by molecular genetic testing.
  • The mother has known α-thalassemia trait with a loss of two α-globin genes in cis (e.g., --/αα) 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 α-thalassemia pathogenic variants.

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 α-thalassemia variant; if the known α-thalassemia variant is present, globin chain synthesis analysis is performed using a fetal blood sample obtained by percutaneous umbilical blood sampling (PUBS).

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
  • My46 Trait Profile
  • NCBI Genes and Disease
  • Thalassaemia International Federation (TIF)
    PO Box 28807
    Nicosia 2083
    Cyprus
    Phone: +357 22 319129
    Fax: +357 22 314552
    Email: thalassaemia@cytanet.com.cy

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

Table B.

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

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

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 two pseudogenes (HBZP [ψ-ζ] and HBAP1 [ψ-α1]). HBD (ψ-α2), previously considered a pseudogene, was recently demonstrated to produce mRNA, although a very little amount [Goh et al 2005]. A θ gene (HBQ1) with an unknown function is located at the 5' end of the cluster (see Figure 2).

Figure 2. . Diagram of the α-globin gene cluster.

Figure 2.

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); ψα1, HBD (previously called ψα2), (more...)

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 (see Figure 2).

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 inactivation of HBA1 or HBA2, and for the pathophysiology of the deletion and non-deletion pathogenic 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 2). 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.

Pathogenic Variants

See Table 3. Deletion of HBA1 and/or HBA2 is the most common cause of α-thalassemia.

Deletion of two α-goblin genes in cis. Different deletions varying from approximately 6 kb to more than 300 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 of these deletions are founder variants 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, -(α)5.2 and -(α)20.5, remove HBA2 and part of HBA1 [Higgs 2001].
  • A deletion removing HBA1 and the theta gene (HBQ1) extends downstream centromeric from the α-globin gene cluster. 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].
  • Several deletions of the HS-40 region also result in the silencing of the intact α-globin genes [Higgs 2001, Coelho et al 2010, Sollaino et al 2010, Wu et al 2016].

Deletion of one α-goblin gene. 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 variants are referred to respectively as the 3.7-kb rightward deletion (-α3.7) and the 4.2-kb leftward deletion (-α4.2) (see Figure 2):

  • 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 recombination 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.

Non-deletion α-thalassemia. Less frequently, α-thalassemia results from single-nucleotide variants 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., αT Saudi). Considered as a group, the non-deletion α-thalassemia variants 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 variants 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 single-nucleotide variant, 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: variants involving RNA splicing, the polyadenylation signal, the initiation of mRNA translation, as well as missense variants of the termination, in-frame deletions, frame-shift variants, and nonsense variants. Variants 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 (see Table 6) [Higgs 2001].

The most common non-deletion variant, which is frequently seen in Southeast Asia, is HbConstant Spring (HbCS), resulting from a nucleotide change in the stop codon of HBA2. This variant 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, result in α-thalassemia trait.

Some of the variants 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 6.

Selected HBA1 and HBA2 Pathogenic Variants

DNA Nucleotide Change 1Predicted Protein Change 1, 2
(Conventional Nomenclature 3)
Common Name2Reference Sequences
HBA2: c.2T>CHBA2: p.Met1ThrαNcoINM_000517​.4
NP_000508​.1
HBA2: c.377T>CHBA2: p.Leu126Pro
(Alpha2 Leu125Pro)
HbQuong Sze
HBA2: c.427T>CHBA2: p.Ter143Glnext32
(Alpha2 142, Stop>Gln)
HbConstant Spring (HbCS)
HBA2: c.94_95delAGHBA2: p.Arg32AspfsTer24
(The deletion of 2 nucleotides causes a frameshift & premature termination at codon [TAA])
HBA2: c.[339C>G; 340_351delCTCCCCGCCGAG]HBA2: p.[His113Gln; Leu114_Glu117del]
(Alpha2 His112Gln and deletion of codons 113-116 -Leu-Pro-Ala-Glu)
HbLleidaNM_000517​.4
NP_000508​.1
HBA2: c.95+2_95+6delTGAGG--αHphI
HBA1: c.223G>CHBA1: p.Asp75Gly
(Asp74Gly)
HbQ-ThailandNM_000558​.3
NP_000549​.1
HBA2: c.207C>G
or HBA1: 207C>A
HBA2 or HBA1: p.Asn69Lys
(Asn68Lys)
HbG PhiladelphiaNM_000517​.4
NP_000508​.1
HBA2: c.*94A>GαTSaudi
HBA2: c.[-2_-3delAC; -α3.74Deletion of HBA2 and of nucleotides that additionally impair translation of the remaining HBA1
3.7Deletion of HBA2Z84721​.1
4.2Deletion of HBA2
-(α)5.2Deletion of HBA2 and 5’ end of HBA1 5
-(α)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.

1.

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.

2.

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

3.

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

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.
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 deletion of one α-globin gene is reduced production of α-globin chains by the affected chromosome (α-thalassemia silent carrier; -α/αα). For example, measurement of α-globin mRNA indicates that the -α4.2 variant is not associated with a compensatory increase in expression in the remaining HBA1, whereas with the -α3.7 variant, the remaining HBA1 expression is roughly halfway between that of normal HBA2 and HBA1 (see Figure 2).

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]
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  3. Taher A, Vichinsky E, Musallam K, Cappellini MD, Viprakasit V. Guidelines for the Management of Non Transfusion Dependent Thalassaemia. Weatherall D, ed. Thalassaemia International Federation. Available online. 2013. Accessed 12-21-16.

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Chapter Notes

Author Notes

Antonio Cao, MD (1929-2012)

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

Renzo Galanello, MD (1948-2013)

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

Author History

Antonio Cao, MD; Consiglio Nazionale delle Ricerche (2005-2012)
Renzo Galanello, MD; Ospedale Regionale Microcitemie (2005-2013)
Paolo Moi, MD (2013-present)
Raffaella Origa, MD (2013-present)

Revision History

  • 29 December 2016 (sw) Comprehensive update posted live
  • 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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