Alpha-Thalassemia

Excerpt

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.