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Alpha-Thalassemia.

Authors

Origa R1, Moi P1.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2005 Nov 1 [updated 2016 Dec 29].

Author information

1
Dipartimento di Scienze Mediche e Sanità Pubblica, Università degli Studi di Cagliari, Ospedale Regionale per le Microcitemie, Cagliari, Italy

Excerpt

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 incis (--/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 incis (--/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 incis 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 incis (--/αα) when the other parent is either unknown or unavailable for testing.

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