Clinical characteristics.

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

Hb Bart syndrome, the more severe form, is characterized by prenatal onset of generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common. Death usually occurs in the neonatal period.

HbH disease has a broad phenotypic spectrum: 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 have enlargement of the spleen (and less commonly of the liver), mild jaundice, and sometimes thalassemia-like bone changes. Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to infections or exposure to oxidant drugs.

Diagnosis/testing.

The diagnosis of Hb Bart syndrome is established in a fetus with characteristic hematologic and hemoglobin (Hb) findings and molecular genetic testing that identifies biallelic pathogenic variants in both HBA1 and HBA2 that result in deletion or inactivation of all four α-globin alleles.

The diagnosis of HbH disease is established in a proband with hematologic and Hb findings and molecular genetic testing that identifies biallelic pathogenic variants in HBA1 and HBA2 that result in deletion or inactivation of three α-globin alleles.

Management.

Treatment of manifestations: Hb Bart syndrome: intrauterine blood transfusions, improved transfusion strategies, and rarely curative hematopoietic stem cell transplant may allow survival of children. HbH disease: while most individuals are clinically well and survive without any treatment, 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. In contrast, persons with non-deletional HbH disease may be more severely affected and transfusion dependent.

Prevention of primary manifestations: Because of the severity of Hb Bart syndrome, the occasional presence of congenital anomalies, and the risk for maternal complications, prenatal testing and early termination of pregnancies at risk have 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 persons with HbH disease: inappropriate iron therapy and oxidant drugs (i.e., the same drugs to be avoided by individuals with glucose-6-phosphate dehydrogenase deficiency).

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.

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

HbH disease: The risk to sibs of a proband depends on genotype of the parents.

Carrier testing: 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 and preimplantation genetic 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.

Suggestive Findings

Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb bart) syndrome (deletion/inactivation of all four alpha globin [α-globin] genes; --/--), and hemoglobin H (HbH) disease (most frequently caused by deletion/inactivation of three α-globin genes; --/-α) (see Figure 1).

Figure 1.

Schematic presentation of the chromosomal location of the alpha globin gene cluster on chromosome 16p. The genes are indicated as boxes; gene symbols are above and the hemoglobin is expressed below. The alpha globin regulatory region (MCS-R1 to -R4; also (more...)

Hb Bart syndrome should be suspected in the following:

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

HbH disease should be suspected in an infant or child with the following clinical or newborn screening findings:

• Clinical findings
  • Mild jaundice
  • Hepatosplenomegaly
  • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences)
• Newborn screening findings. 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. (2) Reference ranges may vary among laboratories performing newborn screening. (3) Low concentrations of Hb Bart (1%-8%) are indicative of the carrier states, and while this finding usually does not indicate a need for further evaluation of the newborn, genetic counseling may be recommended for the parents of the newborn [Ferguson 2018, Fogel et al 2018].

Establishing the Diagnosis

The diagnosis of Hb Bart syndrome is established in a fetus based on the following:

• Hematologic findings
  • 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 >60%
  • Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells
• Hemoglobin analysis that reveals decreased amounts or complete absence of hemoglobin A and increased amounts of Hb Bart (See Table 2.)
• Molecular genetic testing that identifies biallelic pathogenic variants in both HBA1 and HBA2 that result in deletion or inactivation of all four α-globin alleles (e.g., homozygous deletion of both HBA1 and HBA2 on both chromosomes; --/--; see Table 3), which confirms the diagnosis and allows for family studies

The diagnosis of HbH disease is established in a proband based on the following:

• Hematologic findings
  • 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 rarely nucleated red blood cells (i.e., erythroblasts)
  • Red blood cell supravital stain showing HbH inclusions (β₄ tetramers) in 5%-80% of erythrocytes following incubation of fresh blood smears with 1% brilliant cresyl blue for one to three hours
• Hemoglobin analysis that reveals presence of 0.8%-40% HbH and 60%-90% hemoglobin A (See Table 2.)
• Molecular genetic testing that identifies biallelic pathogenic variants in both HBA1 and HBA2 that result in deletion or inactivation of three α-globin genes (e.g., a deletion of two globin alleles in trans with a deletion of one α-globin allele; --/-α^3.7) (see Table 3), which confirms the diagnosis and allows for family studies

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 alpha globin (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 30-40 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. 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 newborns 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; however, clinical features are usually only diagnosed during routine hematologic analysis in an asymptomatic individual.

The majority of individuals have 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 affect 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, infection with parvovirus B19 can cause an aplastic crisis.

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 resulting from 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 beta globin chain 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 (--/--)
• Rarely, an individual with Hb Bart syndrome will have a non-deletion variant (--/α^ND-).

HbH disease

• Most often caused by a large deletion on one allele in trans with a single α-globin gene deletion (--/-α) or other non-deletion inactivating variant (--/α^NDα or --/αα^ND)
• Individuals homozygous for HBA2 pathogenic variants (α^NDα/α^NDα) may have HbH disease.
• Individuals who are homozygous or compound heterozygous for highly unstable α-globin gene variants may have HbH disease.
• Rarely, HbH disease is caused by compound heterozygosity for an MCS-R2 (see Nomenclature and Figure 1) deletion and an additional alpha gene deletion [(αα)^MCS-R2/-α] [Coelho et al 2010, Sollaino et al 2010].

Nomenclature

The α-thalassemia carrier states have been classified on the basis of the total globin protein produced from each of the two α-globin genes and by the number of globin genes that are missing or abnormal (see Table 4).

Genotype nomenclature. In the expression αα/αα, the first alpha in each pair (αα/αα) typically refers to HBA2 and the second alpha in each pair (αα/αα) to HBA1.

The terms "α-thalassemia 1" and "α-thalassemia 2" (referring to α-thalassemia silent carrier and α-thalassemia trait, respectively) are no longer in use [Weatherall et al 1988].

MCS-R2, a multispecies conserved sequence previously known as HS-40, is a cis-acting regulatory element about 40 kb upstream of HBZ that is required for α-globin expression [reviewed by Farashi & Harteveld 2018] (see Figure 1).

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.

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

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, chromosome 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 α-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 testes, 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 a hemizygous ATRX variant in affected males 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 HbH inclusions (β₄ tetramers) in erythrocytes following incubation of fresh blood smears with 1% brilliant cresyl blue. In ATRX syndrome, the alpha globin gene cluster and the MCS-R1-4 regulatory regions of chromosome 16 are structurally intact (see Figure 1).

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 (α⁰-Thalassemia and α⁺-Thalassemia)

Beta-thalassemia. Microcytosis and hypochromia are present in α⁰-thalassemia carriers, hematologically manifesting α⁺-thalassemia carriers, and β-thalassemia carriers. Of note, β-thalassemia carriers are distinguished by a high percentage of HbA₂.

Iron deficiency anemia. Alpha-thalassemia trait can be confused with iron deficiency anemia because mean corpuscular volume and mean corpuscular hemoglobin 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. Although some overlap with α-thalassemia carrier states exists, iron deficiency anemia is characterized by a marked increase in red blood cell distribution width, a quantitative measure of red blood cell anisocytosis. Iron studies (serum iron concentration, transferrin saturation, and serum ferritin) can be used to diagnose iron deficiency anemia with certainty. Iron deficiency and α-thalassemia can coexist, complicating diagnosis.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with alpha-thalassemia (α-thalassemia), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome. See Prenatal Testing and Preimplantation Genetic 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 at presentation because of varying severity
• Referral to a hematologist
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of α-thalassemia in order to facilitate medical and personal decision making

Treatment of Manifestations

Hb Bart syndrome was previously considered a universally fatal condition; however, its prognosis is shifting because of prenatal testing, intrauterine blood transfusions, improved transfusion strategies, and (rarely) curative hematopoietic stem cell transplantation [Pecker et al 2017]. In an international registry, 39 of 69 infants were alive; however, 40%-50% of survivors had growth restriction and 20% had neurodevelopmental delay; congenital anomalies were common. Most affected individuals required lifelong transfusion [Songdej et al 2017]. Individuals with the most severe forms of non-deletional HbH disease may become transfusion dependent (HbH hydrops) and should be managed similarly to those with β-thalassemia major [Taher et al 2017].

More recently, Schwab et al [2023] found that in utero transfusions were associated with earlier resolution of hydrops, delivery closer to term, and better neurodevelopmental outcomes.

Because such advances in intrauterine and postnatal therapy often result in ethical dilemmas for the family and health care provider, consultation with a clinical ethics service may be helpful in assessing health care decisions in the context of the best interest of the child and the values and preferences of the family.

HbH disease. Most individuals with HbH disease are clinically well and survive without any treatment. Individuals with non-deletional HbH disease who have biallelic HBA2 pathogenic variants (e.g., α^{Constant Spring}α/α^{Constant Spring}α) may be more severely affected and, thus, be transfusion dependent.

• Individuals with deletional HbH disease may need occasional red blood cell transfusions if the hemoglobin (Hb) level suddenly drops because of hemolytic or aplastic crises.
• 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 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 transplantation 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 for hemolytic/aplastic crisis (similar to G6PD deficiency, hemolysis in HbH disease can be triggered by oxidative stresses or infection).

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, shown to be superior to placebo in reducing liver iron concentration in those older than age ten years with β-thalassemia intermedia, hemoglobin E/β-thalassemia, or 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 for overwhelming sepsis caused by encapsulated organisms. Use of antimicrobial prophylaxis notwithstanding, a careful clinical evaluation of individuals who have undergone splenectomy and have a fever is recommended.

Surveillance

HbH disease

• Hematologic evaluation every six to 12 months to determine the steady state levels of Hb
• 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 noninvasive quantitative measurement of liver iron concentration by MRI is also recommended [Musallam et al 2012].

Agents/Circumstances to Avoid

HbH disease. Avoid the following:

• Inappropriate iron therapy
• Oxidant drugs according to recommendations for G6PD deficiency [Bubp et al 2015] (full text; note especially Table 1. Drugs To Be Avoided by G6PD-Deficient Patients, and Table 2. Drugs To Be Used With Caution in Therapeutic Doses for Patients With G6PD Deficiency).

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 management (including agents/circumstances to avoid) can be implemented. Evaluations can include:

• Evaluation of red blood cell indices, red blood cell supravital stain for HbH inclusions, and hemoglobin analysis by high-performance liquid chromatography
• Targeted molecular analysis if the pathogenic variants in the family are known
• Molecular genetic analysis (according to the frequency of alpha globin gene pathogenic variants by 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, complications reported in women with HbH disease include worsening of anemia (with occasional need for 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 in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

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

Risk to Family Members

Population Screening for α-Thalassemia Trait

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 testing, 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.

Note: Since --^SEA/--^SEA deletions spare HBZ (zeta globin gene), a fetus has 10%-20% Portland Hb (which is capable of O₂ delivery to tissues) and will survive until the third trimester. However, a fetus with deletion of all four α-globin genes that includes HBZ, such as --^FIL/--^FIL, will nevertheless succumb to hypoxia and heart failure in utero or shortly after birth.

Note: Prospective identification of α-thalassemia silent carriers (i.e., -α/αα or αα^ND/αα) 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies. Prenatal testing and preimplantation genetic testing are 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, --/α^ND-).

Ultrasound examination. Ultrasonography can 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 an α-thalassemia trait with a two-gene deletion in cis (--/αα) and the other has an α-thalassemia-like hematologic picture but no α-thalassemia variant identified by molecular genetic testing.
• The mother has a known α-thalassemia trait with a two-gene deletion in cis (--/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 instances, the options for prenatal testing should be discussed in the context of formal genetic counseling. Analysis of fetal DNA for the known α-thalassemia variant is recommended as the first step in prenatal testing for indeterminate-risk pregnancies; 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Mechanism of disease causation. Normally each individual has four alpha globin (α-globin) genes, i.e., HBA1 and HBA2 on both number 16 chromosomes. Inactivation of HBA1 or HBA2 reduces production of α-globin chains; thus, the more α-globin genes inactivated, the fewer α-globin chains are synthesized, leading to an increasing imbalance between α-globin chains and beta globin chains.

The level of transcription of HBA1 and HBA2 differs: HBA2 produces two to three times more α-globin chains than HBA1. This difference has important clinical implications; for example, inactivation of HBA2 results in fewer α-globin chains than inactivation of HBA1.

MCS-R1 to -R4 region. The expression of HBA1 and HBA2 is regulated by the multispecies conserved sequences (MCS-R1 to -R4) region located about 40 kb upstream from the α-globin cluster (see Figure 1). The MCS-R2 region comprises multiple binding sites for transcriptional factors (NF-E2, GATA-1). The deletion of MCS-R2 results in an alpha-thalassemia (α-thalassemia) phenotype in spite of the structural integrity of both α-globin genes [Coelho et al 2010, Sollaino et al 2010, Higgs 2013, Wu et al 2017].

Gene-specific laboratory technical considerations. See Table 9.

Notable variants by genes causing α-thalassemia. The molecular mechanisms leading to the silencing of either HBA1 or HBA2 include variants affecting RNA splicing, polyadenylation signal, and initiation of mRNA translation, as well as missense variants of the stop codon, in-frame deletions, frameshift variants, and nonsense variants. Non-deletion variants of α-globin genes resulting in the production of hyper-unstable globin variants such as Hb Quong Sze are unable to assemble into stable β₄ tetramers and thus are rapidly degraded, and may also result in α-thalassemia [Higgs 2013].

Author Notes

Hannah Tamary, MD, was the head of Hematology Unit in Schneider Children's Medical Center of Israel for more than 20 years. Currently she is the director of the Pediatric Molecular Hematology Laboratory there, the only laboratory in Israel using next-generation sequencing technology and providing diagnosis for all types of anemias, as well as inherited predisposition to myelodysplastic syndrome/leukemias and bone marrow failure syndromes. She also investigates erythropoiesis through the study of congenital dyserythropoietic anemia.

Author History

Antonio Cao, MD; Consiglio Nazionale delle Ricerche (2005-2012)
Orly Dgany, PhD (2020-present)
Renzo Galanello, MD; Ospedale Regionale Microcitemie (2005-2013)
Paolo Moi, MD; Università degli Studi di Cagliari (2013-2020)
Raffaella Origa, MD; Università degli Studi di Cagliari (2013-2020)
Hannah Tamary, MD (2020-present)

Revision History

• 23 May 2024 (aa) Revision: Schwab et al [2023] added to Treatment of Manifestations
• 1 October 2020 (bp) Comprehensive update posted live
• 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 live
• 3 January 2005 (rg) Original submission

Published Guidelines / Consensus Statements

• Taher A, Musallam K, Cappellini MD, eds. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT). 2 ed. Nicosia, Cyprus: Thalassaemia International Federation; 2017. Available online. Accessed 7-13-23.

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