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.