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 alleles (--/--), and hemoglobin H (HbH) disease, most frequently caused by deletion/inactivation of three alpha globin alleles (--/-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. If untreated, death usually occurs during embryonic life or 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. Individuals may have enlargement of the spleen and mild jaundice. 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 alpha globin alleles.

The diagnosis of HbH disease is established in a proband with characteristic 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 alpha globin alleles.

Management.

Treatment of manifestations: Hb Bart syndrome: intrauterine blood transfusions followed by regular postnatal blood transfusions. If a suitable donor is available, hematopoietic stem cell transplantation should be considered, as it offers a potentially curative treatment and may allow long-term survival.

HbH disease: while most individuals are clinically well and survive without any treatment, occasional hemolytic crises may develop, especially during infection. Individuals should be carefully monitored during these episodes and red blood cell transfusions administered if required. Individuals with non-deletional HbH disease may be more severely affected, and some are transfusion dependent. Even without regular transfusions, iron overload develops in HbH disease due to increased iron absorption secondary to anemia. Monitoring of iron overload is required in all individuals with HbH disease, and iron chelation should be initiated according to available guidelines. Due to the hemolytic component of the disorder, gallstones may develop and cholecystectomy might be needed. Folic acid supplementation is required. Splenectomy is usually avoided due to thromboembolic complications.

Surveillance: In individuals with 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 noninvasive quantitative measurement of liver iron concentration by MRI.

Agents/circumstances to avoid: In individuals 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: 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.

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: If both parents are known to have an --/αα genotype, each sib of a proband with Hb Bart syndrome has at conception a 25% chance of having Hb Bart syndrome, a 50% chance of having α-thalassemia trait, and a 25% chance of being unaffected and not a carrier. If one parent is known to have an --/αα genotype and the other parent is known to have HbH disease, each sib of a proband has at conception a 25% chance of having Hb Bart syndrome, a 25% chance of having HbH disease, a 25% chance of having α-thalassemia trait, and a 25% chance of being a silent carrier.

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

Carrier testing: Evaluations to detect α-thalassemia trait and α-thalassemia silent carrier status in at-risk relatives of an individual with Hb Bart syndrome or HbH disease include molecular genetic testing (if the HBA1 and HBA2 pathogenic variants in the family are known) and Hb analysis.

Prenatal and preimplantation genetic testing: Once the HBA1 and HBA2 pathogenic variants have been identified in a proband with Hb Bart syndrome or HbH disease, prenatal and preimplantation genetic testing are possible.

Population screening for α-thalassemia trait: Because of the high carrier rate for the two-gene deletion on the same chromosome 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.

Suggestive Findings

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 alleles (--/--), and hemoglobin H (HbH) disease, most frequently caused by deletion/inactivation of three alpha globin alleles (--/-α) (see Figure 1).

Figure 1.

Schematic representation 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 MCS-R4; (more...)

Hb Bart syndrome should be suspected in the following situations:

• 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 (NBS) 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)
• NBS findings. Hb Bart >15% at birth identified by analysis of dried blood spots for hemoglobin (Hb) type using high-performance liquid chromatography or isoelectric focusing
  Note: (1) NBS 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 NBS. (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 blood cells, severe anisopoikilocytosis, and numerous nucleated red blood cells
• Hb analysis that reveals decreased amounts or complete absence of hemoglobin A (HbA) 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 alpha globin alleles (e.g., homozygous deletion of both HBA1 and HBA2 on both chromosomes, or --/--) (See Table 3.)
  Note: This 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
• Hb analysis that reveals presence of 0.8%-40% HbH and 60%-90% HbA (See Table 2.)
• Molecular genetic testing that identifies biallelic pathogenic variants in both HBA1 and HBA2 that result in deletion or inactivation of three alpha globin alleles (e.g., a deletion of two alpha globin alleles on one chromosome with a deletion of one alpha globin allele on the opposite homologous chromosome, or --/-α^3.7) (See Table 3.)
  Note: This 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 the alpha 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 blood 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.

Deficient 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, prenatal hemorrhage, and premature delivery.

HbH disease. The clinical phenotype of HbH disease is variable. Individuals with HbH disease caused by deletions only generally maintain good health and often require no treatment. Affected children demonstrate normal growth and development; splenomegaly is either absent or mild, and skeletal changes due to ineffective erythropoiesis are usually not observed. However, hemolytic crises may occur, triggered by infections or inflammatory disorders associated with increased oxidative stress. Exposure to oxidative drugs may also trigger these hemolytic episodes. Under such circumstances increased precipitation of HbH leads to secondary red blood cell damage, and the rapid clearance of those damaged cells results in acute decline in hemoglobin (Hb) levels.

HbH disease caused by non-deletional alpha globin pathogenic variants is generally associated with more severe impairment of alpha globin synthesis and greater ineffective erythropoiesis, resulting in a more severe clinical phenotype. Individuals typically present with more pronounced anemia, and jaundice and splenomegaly are common. Hemolytic crises occur more frequently compared to those with HbH disease due to deletions. The age at diagnosis is usually earlier, often between age 1.5 and 3.5 years, and approximately one third of individuals become transfusion dependent. Iron overload is also more pronounced, and secondary endocrine complications occur more frequently (e.g., hypogonadism, hypothyroidism, and diabetes mellitus).

Individuals with HbH disease may develop gallstones. Rarely, infection with parvovirus B19 can cause an aplastic crisis.

Due to increased intestinal iron absorption driven by ineffective erythropoiesis, individuals with HbH disease may develop iron overload even in the absence of regular transfusions [Chan et al 2021]. Iron-related cardiac or endocrine complications are rare in HbH disorder. However, hepatic iron overload may still be clinically significant, as studies in non-transfusion-dependent beta-thalassemia have linked it to hepatic fibrosis and rarely to hepatocellular carcinoma [Taher et al 2025b]. Therefore, regular monitoring of liver iron accumulation and appropriate measures to prevent iron overload are essential [Amid et al 2023].

Fertility may also be affected, although data in non-transfusion-dependent α-thalassemia remain scarce; notably, while most individuals with HbH disease are largely asymptomatic, anemia can worsen during physiologic stress such as pregnancy, occasionally necessitating transfusion, and thus regular prenatal care is recommended to optimize outcomes [De Sanctis et al 2014, Chuncharunee et al 2019, Ake-Sittipaisarn et al 2022, Lal et al 2024].

Thalassemia syndromes are characterized by a hypercoagulable state, with splenectomy acting as a major amplifying risk factor. Consistent with the broader thalassemia literature, thromboembolic complications are most strongly associated with the combination of splenectomy and ongoing anemia, supporting routine post-splenectomy thromboprophylaxis with low-dose aspirin to reduce thromboembolic events, which is particularly recommended following splenectomy in individuals with non-deletional HbH disease given their heightened risk profile [Succar et al 2011, Cappellini et al 2012, Chansai et al 2018, Lal et al 2024].

Genotype-Phenotype Correlations

The phenotype of the α-thalassemia syndromes depends on the degree of alpha globin chain deficiency relative to beta globin chain production. The correlation between α-thalassemia pathogenic variants, alpha globin mRNA levels, alpha globin synthesis, and clinical manifestations of α-thalassemia is well documented.

Hb Bart syndrome

• Most often caused by large deletions of both HBA1 and HBA2 on both chromosomes (--/--)
• Rarely, an individual with Hb Bart syndrome will have a non-deletion variant (e.g., --/α^T-).

HbH disease

• Most often caused by a large deletion of both HBA1 and HBA2 on one chromosome with a single alpha globin allele deletion (e.g., --/-α) or other non-deletion inactivating variant (e.g., --/α^Tα) on the opposite homologous chromosome
• Individuals homozygous for HBA2 pathogenic variants (α^Tα/α^Tα) may have HbH disease.
• Individuals who are homozygous or compound heterozygous for highly unstable alpha globin gene pathogenic 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 globin allele deletion on the opposite homologous chromosome (e.g., α^MCS-R2α^MCS-R2/-α) [Coelho et al 2010, Sollaino et al 2010].

Nomenclature

Alpha-thalassemia carrier states with corresponding genotypes and globin protein production are listed in Table 4.

Alpha-thalassemia silent carrier status may also be referred to as α-thalassemia minima.

Alpha-thalassemia trait may also be referred to as α-thalassemia minor.

Hemoglobin H (HbH) disease may also be referred to as α-thalassemia intermedia.

Hemoglobin Barts hydrops fetalis (Hb Bart) syndrome survivors are considered to have α-thalassemia major.

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) refers to HBA1.

MCS-R2, a multispecies conserved sequence regulatory region previously known as HS-40, is a regulatory element about 40 kb upstream of HBZ that is required for alpha 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 percentage 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 genetic testing. For detailed references for the frequency of α-thalassemia in each population, see Piel & Weatherall [2014].

Clinically significant α-thalassemia is common in Asia and the Mediterranean region; population migration has led to a rising prevalence in many countries worldwide.

A systematic literature review of studies published between 2000 and 2021 evaluated the global and birth prevalence of clinically significant α-thalassemia and beta-thalassemia (β-thalassemia) [Musallam et al 2023]. Out of 70 included publications, only eight reported population-based estimates for α-thalassemia, with data from North America, Europe, and Asia (Malaysia). The prevalence of α-thalassemia in the United States and Canada ranged from 0.04:100,000 individuals (in 2001-2004) to 0.6:100,000 (in 2004-2008), and from 0.03:100,000 in Spain to 4.5:100,000 in Malaysia.

Africa

• The highest allele frequency (0.30-0.40) of the -α^3.7 allele has been observed in the equatorial belt including Nigeria, Ivory Coast, and Kenya.
• Deletion of both HBA1 and HBA2 on the same chromosome (--/αα) has been reported very rarely in North Africa and in the African American population.

Mediterranean

• Alpha-thalassemia trait caused by two -α^3.7 deletions is common, with the highest allele frequency reported in Sardinia (0.18) and the lowest in Spain.
• Deletion of both HBA1 and HBA2 on the same chromosome (--/αα) is very rare (0.002); thus, Hb Bart syndrome 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.

Arabian Peninsula

• Frequency of the -α^3.7 allele (causing α-thalassemia trait) varies from 0.01 to 0.67, with the highest values being observed in Oman.
• Deletion of both HBA1 and HBA2 on the same chromosome (--/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 -α^3.7 allele and the -α^4.2 allele variably contribute to incidence of α-thalassemia trait.
• Deletion of both HBA1 and HBA2 on the same chromosome (--/αα) is very rare.

Southeast Asia

• Common deletions of both HBA1 and HBA2 (--^SEA, --^THAI, --^FIL) and deletions of one alpha globin allele (-α) are very common, causing a major public health burden.
• Alpha-thalassemia caused by Hb Constant Spring alleles (α^{Constant Spring}α/α^{Constant Spring}α), a non-deletion pathogenic variant in HBA2, is also common.
• The incidence of Hb Bart syndrome is expected to be in the range of 0.5-5:1,000 births and HbH disease in the range of 4-20:1,000 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 α-thalassemias have unusual mutation mechanisms; for example, some affected individuals on the island of Vanuatu who have normal alpha 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].
• Deletion of both HBA1 and HBA2 on the same chromosome (--/αα) is very rare.

Hydrops Fetalis

Hydrops fetalis is associated with many conditions in addition to hemoglobin Bart hydrops fetalis (Hb Bart) syndrome, 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 (Hb) 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, glucose-6-phosphate dehydrogenase deficiency). See Phillips & Henderson [2018] for review.

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by a hemizygous ATRX pathogenic variant and inherited in an X-linked manner. Transcriptional regulator ATRX is a widely expressed transcriptional regulation protein and plays a role in chromatin remodeling. ATRX loss can cause alpha-thalassemia (α-thalassemia) due to the downregulation of the alpha globin gene cluster. ATRX also acts as a tumor suppressor. Other clinical characteristics of ATR-X syndrome include distinctive craniofacial features, intellectual disability, hypotonia, minor skeletal anomalies, and urogenital anomalies. Data suggest that intellectual disability may be the only clinical sign shared by all individuals with ATR-X syndrome and that few individuals develop osteosarcoma [León & Harley 2021].

Acquired α-thalassemia (α-thalassemia-myelodysplastic syndrome; ATMDS) is a rare, non-inherited form of α-thalassemia that develops secondary to a clonal hematologic disorder, most commonly myelodysplastic syndrome (MDS). Acquired α-thalassemia arises due to somatic pathogenic variants, most frequently in ATRX. These pathogenic variants lead to downregulation of alpha globin gene expression within the malignant hematopoietic clone and result in a phenotype similar to HbH disease, with microcytic, hypochromic anemia and the presence of HbH on Hb electrophoresis. Clinically, acquired α-thalassemia should be suspected in individuals with MDS or other myeloid neoplasms who develop new-onset microcytic anemia, especially as MDS typically causes normocytic or macrocytic indices. The diagnosis is confirmed by demonstrating HbH on electrophoresis and excluding germline alpha globin gene pathogenic variants [León & Harley 2021].

Alpha-Thalassemia Trait

Beta-thalassemia. Microcytosis and hypochromia are present in individuals with α-thalassemia trait and beta-thalassemia carriers. Note: Beta-thalassemia carriers are distinguished by a high percentage of hemoglobin A₂. Beta-thalassemia is caused by biallelic pathogenic variants in HBB.

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 α-thalassemia trait. 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.

HbH disease

• Differentiation of deletional (mild) from non-deletional (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 clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) 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

Surveillance

Individuals with HbH disease and Hb Bart syndrome survivors

• Hematologic evaluation every six to 12 months to determine the steady state levels of hemoglobin (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

Individuals with HbH disease and Hb Bart syndrome survivors. Avoid the following:

• Inappropriate iron therapy
• Oxidant drugs according to recommendations for glucose-6-phosphate dehydrogenase 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 Hb analysis by high-performance liquid chromatography
• Targeted molecular genetic testing if the pathogenic variants in the family are known
• Molecular genetic testing if the pathogenic variants in the family are not known (See Establishing the Diagnosis, Molecular Genetic Testing.)

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

Pregnancy Management

Pregnancies in individuals with HbH disease are considered a high-risk pregnancy. The physiologic changes in pregnancy leading to an expansion of blood volume can aggravate the severity of anemia. Maternal anemia is associated with adverse pregnancy and neonatal outcomes, such as intrauterine hypoxia leading to fetal growth restriction, low birth weight, and preterm birth. Notably, non-deletional HbH disease has worse pregnancy outcomes than deletional HbH disease[Ake-Sittipaisarn et al 2022]. Monitoring for these possible complications is recommended.

Therapies Under Investigation

Targeting ineffective erythropoiesis in HbH disease. An ongoing Phase II trial (NCT05664737) is evaluating the efficacy of luspatercept for the treatment of anemia in adults and adolescents with α-thalassemia. Luspatercept is an erythroid maturation agent. In 2026, the study met its primary endpoints in adults; in the non-transfusion-dependent cohort, treatment resulted in a mean Hb increase of >1 g/dL over 12 weeks, while in the transfusion-dependent cohort a >50% reduction in transfusion burden was achieved [Viprakasit et al 2023, Lai et al 2025].

In utero hematopoietic stem cell transplantation (IUHSCT) for α-thalassemia major. A Phase I trial (NCT02986698) evaluated IUHSCT using maternal CD34⁺ cells administered during pregnancy but was terminated in early 2026 after interim analyses demonstrated insufficient efficacy. Although the procedure was technically feasible and well tolerated for both mother and fetus, maternal cell engraftment levels were inadequate to achieve the predefined therapeutic endpoints.

Gene therapy for Hb Bart syndrome. Lentiviral gene-addition strategies delivering functional alpha globin genes to autologous hematopoietic stem and progenitor cells (HSPCs) have demonstrated correction of globin imbalance in preclinical models [Segura et al 2025]. Early phase clinical trials (NCT05757245, NCT05851105) are currently evaluating the safety and efficacy of lentiviral vectors encoding alpha globin in individuals with α-thalassemia, although no interim clinical data have yet been reported. A mouse model of lethal α-thalassemia was cured by transduction with a lentiviral vector expressing human alpha globin genes [Chappell et al 2024].

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.

Mode of Inheritance

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

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

Parents of a proband

• The parents of a fetus with Hb Bart syndrome typically have α-thalassemia trait associated with an --/αα HBA2 and HBA1 genotype (i.e., deletion or inactivation of two alpha globin genes on the same chromosome [also referred to as α⁰-thalassemia]).
• Less commonly, one parent of a fetus with Hb Bart syndrome has an --/αα genotype and the other parent has hemoglobin H (HbH) disease (e.g., --/-α).
• Molecular genetic testing is recommended for the parents of the proband to establish genetic status of the parents and allow reliable recurrence risk assessment.

Sibs of a proband

• If both parents are known to have an --/αα genotype, each sib of a proband with Hb Bart syndrome has at conception a:
  • 25% chance of having Hb Bart syndrome (e.g., --/--)
  • 50% chance of having α-thalassemia trait (e.g., --/αα)
  • 25% chance of being unaffected and not a carrier (αα/αα)
• If one parent is known to have an --/αα genotype and the other parent known to have HbH disease, each sib of a proband with Hb Bart syndrome has at conception a:
  • 25% chance of having Hb Bart syndrome (e.g., --/--)
  • 25% chance of having HbH disease (e.g., --/-α)
  • 25% chance of having α-thalassemia trait (e.g., --/αα)
  • 25% chance of being a silent carrier (e.g., -α/αα)
• Individuals with α-thalassemia trait are asymptomatic with a moderate thalassemia-like hematologic picture (i.e., mild hypochromic [low mean corpuscular hemoglobin], microcytic [low mean corpuscular volume] anemia and normal hemoglobin A₂ [HbA₂] and hemoglobin F [HbF]).
• Individuals who are silent carriers have a completely silent hematologic phenotype or very mild microcytosis.

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

Other family members. If both parents are known to have an --/αα genotype, each sib of the proband's parents is at a 50% risk of having α-thalassemia trait with deletion or inactivation of two alpha-globin genes on the same chromosome (--/αα).

HbH Disease – Risk to Family Members

Parents of a proband

• The parents of a child with HbH disease usually have different HBA2 and HBA1 genotypes.
• Molecular genetic testing is recommended for the parents of a proband to establish the genetic status of the parents and allow reliable recurrence risk assessment.

Sibs of a proband. The risk to sibs of a proband depends on the genotype of the parents (see Table 5).

• Individuals with α-thalassemia trait are asymptomatic with a moderate thalassemia-like hematologic picture (i.e., mild hypochromic [low mean corpuscular hemoglobin], microcytic [low mean corpuscular volume] anemia and normal HbA₂ and HbF).
• Individuals who are silent carriers have a completely silent hematologic phenotype or very mild microcytosis.

Offspring of a proband. If the HBA2 and HBA1 genotype of the reproductive partner of a proband with HbH disease is αα/αα (i.e., the reproductive partner has only normal hemoglobin), all offspring will be silent carriers or have α-thalassemia trait. (See Related Genetic Counseling Issues, Family planning and Population screening for α-thalassemia trait.)

Other family members of a proband with HbH disease. Depending on the genetic status of the parents of the proband, each sib of the proband's parents is at risk of having α-thalassemia trait (e.g., --/αα or -α/-α) or being a silent carrier (e.g., -α/αα).

Carrier Detection for Individuals with a Positive Family History of Hb Bart Syndrome or HbH Disease

Carrier states and genotype-phenotype correlations for α-thalassemia. See Table 6.

Related Genetic Counseling Issues

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

Family planning

• Given the high carrier rate of α-thalassemia in certain populations (see Prevalence), it is appropriate to offer carrier testing to the reproductive partner of an individual with HbH disease or α-thalassemia trait associated with either deletion of the two alpha globin genes on the same chromosome (--/αα) or a non-deletion pathogenic variant (α^Tα/αα) in HBA2.
• The optimal time for determination of genetic risk 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 with (or at risk of) HbH disease or α-thalassemia trait and young adults who are (or are at risk of being) silent 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

Once the HBA1 and HBA2 pathogenic variants have been identified in a proband with Hb Bart syndrome or HbH disease, prenatal and preimplantation genetic testing are possible.

High risk. Prenatal and preimplantation genetic testing are possible for couples confirmed by molecular genetic testing to be at risk of having a fetus with Hb Bart syndrome (--/-- or --/α^T-) because both parents are carriers of a two-gene deletion on the same chromosome (--/αα) or a deletion and a non-deletion inactivating variant on the same chromosome (e.g., α^T-/αα).

Ultrasound examination 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. An indeterminate-risk pregnancy is a pregnancy for which ONE of the following is true:

• One parent has α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the other has an α-thalassemia-like hematologic picture but no α-thalassemia-related pathogenic variant identified by molecular genetic testing.
• The mother has α-thalassemia trait with a two-gene deletion on the same chromosome (--/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 (see Prevalence).

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 pathogenic variant is recommended in prenatal testing for indeterminate-risk pregnancies.

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

Population screening for α-thalassemia trait

• Because of the high carrier rate for the two-gene deletion on the same chromosome (--/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 (see Prevalence) to identify those at risk of conceiving a fetus with Hb Bart syndrome.
• The American College of Medical Genetics and Genomics includes α-thalassemia among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].
• Note: Since --^SEA/--^SEA deletions spare HBZ (zeta globin gene), a fetus has 10%-20% Hb Portland (which is capable of oxygen delivery to tissues) and will survive until the third trimester. However, a fetus with deletions of all four alpha globin alleles that includes HBZ, such as --^FIL/--^FIL, will succumb to hypoxia and heart failure in utero or shortly after birth.

Prospective identification of α-thalassemia silent carriers (e.g., -α/αα or αα^T/αα) is not strongly indicated, as the offspring of these carriers are not at risk for Hb Bart syndrome.

Molecular Pathogenesis

Mechanism of disease causation. Normally each individual has four alpha globin alleles, that is, HBA1 and HBA2 on both number 16 chromosomes. Inactivation of HBA1 or HBA2 reduces production of alpha globin chains; thus, the more alpha globin alleles inactivated, the fewer alpha globin chains synthesized, leading to an increasing imbalance between alpha globin chains and beta globin chains.

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

Multispecies conserved sequences (MCS) regulatory region 1 (R1) to R4. The expression of HBA1 and HBA2 is regulated by the MCS-R1 to MCS-R4 region located about 40 kb upstream from the alpha globin cluster (see Figure 1). MCS-R2 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 alpha 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 in 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 alpha 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. She founded and was 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. Currently she is a consultant hematologist and researcher in Safra Children's Hospital in Sheba Medical Center in Israel. Her research interests include 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)
Noa Greenberg-Kushnir, MD (2026-present)
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 April 2026 (sw) Comprehensive update posted live
• 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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