Autosomal Recessive
Principles
• Heterozygote advantage
• Ethnic variation in allele frequencies
• Gene dosage
• Compound heterozygote
Major Phenotypic Features
• Age at onset: Childhood
• Hypochromic microcytic anemia
• Hepatosplenomegaly
• Extramedullary hematopoiesis
History and Physical Findings
J.Z., a 25-year-old healthy Canadian woman, presented to her obstetrician for routine prenatal care. Results of her complete blood count showed a mild microcytic anemia (hemoglobin, 98 g/L; mean corpuscular volume, 75 µm3). She was of Vietnamese origin, and her spouse, T.Z., was of Greek origin. J.Z. was unaware of any blood disorders in her or T.Z's family. Nonetheless, hemoglobin (Hb) electrophoresis showed a mildly elevated Hb A2 (α2δ2) and Hb F (α2γ2), which suggested that J.Z. had β-thalassemia trait; molecular testing detected a nonsense mutation in one β-globin allele and no α-globin deletions. The results of T.Z.'s testing showed that he also had a nonsense mutation of one β-globin allele and no α-globin deletions. After referral to the genetics clinic, the geneticist explained to J.Z. and T.Z. that their risk for a child with β-thalassemia major was 25%. After discussing prenatal diagnosis and postnatal prognosis, J.Z. and T.Z. chose to carry the pregnancy to term without further investigation.
Background
Disease Etiology and Incidence
Thalassemias are autosomal recessive anemias caused by deficient synthesis of either α-globin or β-globin. A relative deficiency of α-globin causes α-thalassemia (MIM 141800), and a relative deficiency of β-globin causes β-thalassemia (MIM 613985) (see Chapter 11).
Thalassemia is most common among persons of Mediterranean, African, Middle Eastern, Indian, Chinese, and Southeast Asian descent. Thalassemias appear to have evolved because they confer heterozygote advantage in providing some resistance to malaria (see Chapter 9); the prevalence of thalassemia in an ethnic group therefore reflects past and present exposure of a population to malaria. The prevalence of α-thalassemia trait ranges from less than 0.01% in natives from nonmalarial areas such as the United Kingdom, Iceland, and Japan to approximately 49% among natives of some Southwest Pacific islands; Hb H disease and hydrops fetalis (see Table 11-4) are restricted to the Mediterranean and Southeast Asia. The incidence of β-thalassemia trait ranges from approximately 1% to 2% among Africans and African Americans to 30% in some villages of Sardinia.
Pathogenesis
Thalassemia arises from inadequate hemoglobin production and unbalanced accumulation of globin subunits. Inadequate hemoglobin production causes hypochromia and microcytosis. Unbalanced accumulation of globin causes ineffective erythropoiesis and hemolytic anemia. The severity of thalassemia is proportionate to the severity of the imbalance between α-globin and β-globin production.
More than 200 different mutations have been associated with thalassemia, although only a few mutations account for most thalassemia cases. Deletion of α-globin genes accounts for 80% to 85% of α-thalassemia, and approximately 15 mutations account for more than 90% of β-thalassemia. Molecular studies of both α-globin and β-globin mutations strongly suggest that the various mutations have arisen independently in different populations and then achieved their high frequency by selection.
Phenotype and Natural History
The α-globin mutations are separated into four clinical groups that reflect the impairment of α-globin production (see Table 11-4).
The phenotypes observed in a population reflect the nature of the α-globin mutations in that population. Chromosomes with deletion of both α-globin genes are observed in Southeast Asia and the Mediterranean basin; therefore, Hb H disease and hydrops fetalis usually occur in these populations and not in Africans, who usually have chromosomes with deletion of only one α-globin gene on a chromosome.
The β-globin mutations are also divided into clinical groups reflecting the impairment of β-globin production. β-Thalassemia trait is associated with a mutation in one β-globin allele and β-thalassemia major with mutations in both β-globin alleles. In general, patients with β-thalassemia trait have a mild hypochromic microcytic anemia, mild bone marrow erythroid hyperplasia, and occasionally hepatosplenomegaly; they are usually asymptomatic. Patients with β-thalassemia major present with severe hemolytic anemia when the postnatal production of Hb F decreases. The anemia and ineffective erythropoiesis cause growth retardation, jaundice, hepatosplenomegaly (extramedullary hematopoiesis), and bone marrow expansion (Fig. C-44). Patients usually present within the first 2 years of life, and approximately 80% of untreated patients die by 5 years of age. Patients receiving transfusion therapy alone die before 30 years of infection or hemochromatosis, whereas patients receiving both transfusion therapy and iron chelation therapy usually survive beyond the third decade. Iron overload from repeated transfusions and increased intestinal absorption causes cardiac, hepatic, and endocrine complications.
FIGURE C-44 The typical facial appearance of a child with untreated β-thalassemia. Note the prominent cheekbones and the protrusion of the upper jaw that results from the expansion of the marrow cavity in the bones of the skull and face. See Sources & Acknowledgments.
Management
Initial screening for α- or β-thalassemia trait is usually done by determination of erythrocyte indices. For patients without iron deficiency anemia, the diagnosis of β-thalassemia trait is usually confirmed by finding increased levels of Hb A2 (α2δ2) and Hb F (α2γ2) (which contain other β-like globin chains from the β-globin cluster), or DNA mutation analysis, or both. In contrast, α-thalassemia trait is not associated with changes in Hb A2 or Hb F and is confirmed by DNA mutation analysis or demonstration of a high β-globin/α-globin ratio.
Treatment of Hb H disease is primarily supportive. Therapy includes folate supplementation, avoidance of oxidant drugs and iron, prompt treatment of infection, and judicious transfusion. Splenectomy is rarely required.
Treatment of β-thalassemia includes blood transfusions, iron chelation, prompt treatment of infection, and frequently splenectomy. Bone marrow transplantation is the only currently available cure. Clinical trials are currently under way for drugs that will increase the expression of fetal hemoglobin, which would ameliorate β-thalassemia (but not α-thalassemia) (see Chapter 13).
Inheritance Risk
If each parent has β-thalassemia trait, the couple has a 25% risk for having a child with β-thalassemia major and a 50% risk for having a child with β-thalassemia trait. If one parent has β-thalassemia trait and the other parent a triplication of the α-globin gene, this couple could also have a 25% risk for having a child with β-thalassemia major.
For parents with α-thalassemia trait, their risk for a child with Hb H disease or hydrops fetalis depends on the nature of their α-globin mutations. Parents with α-thalassemia trait can have either the −α/−α or − −/αα genotype (see Chapter 11); therefore, depending on their genotypes, all their children will have α-thalassemia trait (−α/−α), or they may have a 25% risk for having a child with Hb H disease (−α/− −) or hydrops fetalis (− −/− −).
For both α- and β-thalassemia, prenatal diagnosis is possible by molecular analysis of fetal DNA from either chorionic villi or amniocytes. Molecular prenatal diagnosis of thalassemia is most efficient if the mutations have already been identified in the carrier parents. Preimplantation diagnosis has been achieved but requires knowing which mutations might be expected.
Questions for Small Group Discussion
1. A father has the genotype ααα/α−, β/β and a mother αα/αα, β/−. If their child has the genotype α−/αα, β/−, what is the most likely phenotype? Why? If the child's genotype is ααα/αα, β/−, what is the most likely phenotype? Why?
2. What are the molecular mechanisms of α-globin gene deletion? Of α-globin gene triplication?
3. How does expression of γ-globin protect against β-thalassemia?
4. Describe carrier screening for thalassemia. To what ethnic groups should carrier screening be applied? Should individuals from classically low-risk ethnic groups be screened if their partner has α- or β-thalassemia trait? Consider population admixture.
5. α-Thalassemia is the most common single-gene disorder in the world. Three mechanisms can increase the frequency of a mutation in a population: selection, genetic drift, and founder effects. Describe each mechanism and the reason that selection is likely to account for the high frequency of α-thalassemia.
References
Cao A, Galanello R, Origa R. Beta-thalassemia. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1426/.
Cao A, Kan YW. The prevention of thalassemia. Cold Spring Harbor Perspect Med. 2013;3:a011775.
Origa R, Moi P, Galanello R, et al. Alpha-thalassemia. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1435/.