Alpha Thalassemia Clinical Presentation

Updated: Oct 11, 2022
  • Author: Alexandra C Cheerva, MD, MS; Chief Editor: Hassan M Yaish, MD  more...
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History and Physical Examination

The history and physical findings in patients with alpha thalassemia vary according to the number of alpha-globin chains deleted. Additional beta-chain and other hemoglobin abnormalities may also contribute to the clinical presentation and course.

Silent carrier

Silent carriers (-α/αα) are essentially asymptomatic, and complete blood count (CBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), peripheral smear, and hemoglobin electrophoresis are all typically normal. Slight hypochromia and microcytosis may be evident by microscopic evaluation. Silent carriers may be detected by alpha gene analysis. They may be identified when related carriers of the allele mate and have children with hemoglobin H (HbH) disease.

Alpha thalassemia trait

Individuals with alpha thalassemia trait (-α/-α or --/αα) are asymptomatic, with a normal CBC. The peripheral blood smear typically shows hypochromia, microcytosis, and target cells. The MCV is frequently less than 80 fL, and the MCH is always below 27 pg. RBC counts are usually higher than normal. Hemoglobin electrophoresis is normal. Although elevation of hemoglobin A2 does not occur, elevations of hemoglobin F have been reported.

Individuals of African origin usually carry a homozygous state of the alpha2 allele (the trans deletion, -α/-α), and deletion usually involves the less active of 2 normal alleles. Alpha thalassemia trait tends to be milder in this population. In Asia, the cis deletion ( --/αα) is common, and subpopulations exhibit more dramatic features of thalassemia trait. If patients have the hemoglobin Constant Spring (CS) mutation, a slowly migrating abnormal hemoglobin band is present on hemoglobin electrophoresis.

The condition is generally diagnosed as a result of incidental laboratory abnormalities and family studies to characterize a relative. Alpha-globin gene analysis can confirm the absence of 2 alpha-globin genes. Persons with this condition may be identified when a child is born with HbH disease.

Hemoglobin H disease

Symptoms of HbH disease (--/-α) are consistent with a chronic hemolytic anemia and include episodes of severe pallor and anemia. Patients are often symptomatic at birth; many others present with neonatal jaundice or anemia. Indirect hyperbilirubinemia, elevated lactate dehydrogenase levels, and reduced haptoglobin are all consistently seen with hemolytic anemia. Exacerbations of hemolysis may occur when patients are exposed to stressors such as infections, fever, ingestion of oxidative compounds, or drug use, and patients may require transfusions.

Generally, HbH disease is thought to be a mild disorder. However, because of the marked variability in degree of anemia, patients may range from asymptomatic to needing periodic transfusions to having severe anemia with hepatomegaly and splenomegaly. Some patients may also suffer hydrops fetalis syndrome in utero. Pregnancy may also be a special circumstance, in which patients may develop severe anemia and require transfusions. [18] The subset of patients with HbH Constant Spring (CS) may have a high risk of life-threatening anemia and require close follow-up. [19]

Complications occur in varying degrees and include the following:

  • Hepatosplenomegaly

  • Leg ulcers

  • Gallstones

  • Aplastic or hypoplastic crises

  • Skeletal, developmental, and metabolic changes due to ineffective erythropoiesis (these resemble the changes characteristic of beta thalassemia intermedia or beta thalassemia major)

  • Prominent frontal bossing (due to bone marrow expansion)

  • Delayed pneumatization of sinuses

  • Marked overgrowth of the maxillae

  • Ribs and long bones becoming boxlike and convex

  • Premature closure of epiphyses resulting in shortened limbs

  • Compression fracture of the spine (which may result in cord compression or other neurologic deficits)

  • Osteopenia and fractures

Splenectomy or transfusional support is often necessary in the second or third decade of life. Iron overload may also occur as a result of increased iron absorption and frequent transfusions.

Acquired cases are observed in myeloproliferative diseases (eg, acute myelogenous leukemia, erythroleukemia, refractory sideroblastic anemia, acute lymphocytic leukemia).

Hydrops fetalis (alpha thalassemia major)

Individuals with hydrops fetalis (--/--) have no functional alpha-globin chains and thus are unable to make functional hemoglobin. Usually, they die in utero or shortly after birth. Infants who survive to be born have massive total body edema with high-output congestive heart failure due to the severe anemia. They also have massive hepatomegaly due to heart failure and extramedullary hematopoiesis. An excess of hemoglobin Bart’s, which is unable to carry oxygen effectively, is usually present.

There have been several case reports of individuals with hemoglobin Bart’s who have survived for variable amounts of time, but many have developmental abnormalities, and all have undergone intrauterine transfusions and required regular blood transfusion and chelation therapy. In a study of nine patients with hydrops fetalis followed-up for a median period of 7 years, Chan et al noted the occurrence of hypospadias, growth retardation, global developmental delay, and residual neurologic deficits. [28]

Alpha thalassemia mental retardation syndromes

There are 2 clinical entities described in which patients are noted to have mild forms of alpha thalassemia in conjunction with mental retardation: the ATR-16 syndrome and the ATR-X syndrome. [29]

In the ATR-16 syndrome, affected children have large chromosomal rearrangements involving the short arm of the chromosome 16 telomere, which includes the alpha-globin complex. This results in monosomy for the 16p telomere and the alpha-thalassemia phenotype. If an affected child also inherits a single alpha-globin gene deletion from the other parent, HbH disease results. These children may also have mental retardation and other congenital anomalies that are thought to be due to deletions of dose-sensitive genes on chromosome 16p.

The ATR-X syndrome is an X-linked disorder caused by mutations of the ATRX gene located on chromosome Xq13.3. [25] This gene acts as a regulator of alpha-globin gene expression. Patients who are affected have normal alpha-globin genes, but the expression of these genes is downregulated.

The ATR-X syndrome is more common than the ATR-16 syndrome. Males who are affected usually have severe intellectual and physical handicaps and other congenital anomalies. Skeletal deformities are present in as many as 90% of patients. The alpha-thalassemia phenotype varies, with HbH inclusion bodies found in 0-32% of circulating erythrocytes.

Alpha thalassemia myelodysplastic syndrome

A particularly severe acquired form of HbH disease may occur in elderly men with clonal myeloproliferative diseases, in whom HbH levels may be as high as 60%. This disease, commonly referred to as alpha thalassemia myelodysplastic syndrome (ATMDS), is characterized by marked hypochromic microcytic anemia and the presence of HbH as demonstrated by hemoglobin electrophoresis and supravital staining.

ATMDS patients are also found to have a very low ratio of alpha-globin chains to beta-globin chains (α/β ratio), often less than 0.2. This ratio is lower than would be expected for patients with a single functioning alpha-globin gene (--/-α), which suggests downregulation of all 4 alpha-globin genes by a trans -acting mutation. Low alpha-globin messenger RNA levels are found in bone marrow cells.

When archival blood and bone marrow from patients with ATMDS are studied, acquired ATR-X mutations are found in most patients. Hemolytic disease caused by HbH disease may wax and wane over the course of the myeloproliferative disease.



The morbidity and mortality of alpha thalassemia are related to the degree of imbalanced globin production and therefore correlate well with the number of affected alpha-globin genes.

Individuals who are silent carriers (-α/αα) or have alpha thalassemia trait (--/αα or -α/-α) are phenotypically normal or have mild anemia as the only major morbidity associated with their disease. [30]

In patients with HbH disease (--/-α), the degree of anemia varies, and morbidity and mortality are largely related to the degree. As a result of multiple blood transfusions, consequences of iron overload on the heart, liver, and other organs may be present; these can contribute to morbidity and mortality. Patients with HbH disease may develop hypersplenism, gallstones, leg ulcers, frequent infections, and various forms of venous thrombosis.

A study by Chou et al indicated that loss of ATR-X proteins in pancreatic neuroendocrine tumors, due to somatic inactivating mutations in ATRX, independently predicts poor overall survival in patients with these neoplasms. [31]

The most severe form of alpha thalassemia, hemoglobin Bart’s, is characteristic of individuals with no functional alpha-globin genes (--/--). After a gestation of about 33 weeks, these infants develop hydrops fetalis syndrome and may die in utero, during delivery, or shortly after birth. With medical advances, however, survival has been documented.

A study by Bahar et al indicated that persons with alpha thalassemia have a nearly three-fold greater risk for impaired glucose tolerance (ie, diabetes mellitus or prediabetes). The study included 80 alpha-thalassemia carriers and 80 controls, with fasting blood sugar and oral glucose tolerance tests indicating a relative risk of 2.78 for glucose tolerance impairment in the alpha-thalassemia group. [32]

A study by Winichakoon et al found that in nontransfusion-dependent thalassemia, complications associated with alpha thalassemia were less prevalent than, and different from, those related to beta thalassemia. While extramedullary hematopoiesis, cardiomyopathy, cholelithiasis, and pulmonary hypertension occurred more frequently in beta thalassemia, osteoporosis was a more common complication in alpha thalassemia. [33]