Prenatal Screening for Thalassemias

Key Points

Homozygous α ⁰ -thalassemia and β-thalassemia major are global autosomal disorders.
Different α- and β-thalassemia genotypes may be associated with variable phenotypes.
Universal screening is preferred for high-prevalence areas and countries with migrants from high-prevalence areas.
Screening by mean corpuscular volume or mean corpuscular haemoglobin with or without haemoglobin (Hb) pattern is feasible.
Workup for screen-positive couples includes Hb and molecular studies.
Molecular diagnosis of α- and β-thalassemia is useful for diagnosis of carriers with borderline haematologic parameters and for prenatal diagnosis.
Ultrasound exclusion of homozygous α ⁰ -thalassemia can effectively reduce the need for invasive testing in the majority of unaffected pregnancies.
Early screening is preferred. For populations with a high prevalence of α-thalassemia carriers, screening is still advisable in late gestation in view of severe maternal risks associated with homozygous α ⁰ -thalassemia.
Education of health care professionals and community, and counselling with informed consent are essential for effective screening programs.

Introduction

Haemoglobin (Hb) is a tetrameric protein made up of two α-like (α or ζ) and two β-like (ε, γ, δ or β) globin chains ( Fig. 27.1 ). Thalassemias are characterised by the reduced synthesis of the globin chains of Hb. The two most severe forms of thalassemias are homozygous α ⁰ -thalassemia with deletion of four α-globin genes and β-thalassemia major with defects of both β-globin genes ( Tables 27.1 and 27.2 ), which cause major public health problems. Thalassemia is common in Mediterranean area, India, Southeast Asia and sub-Saharan Africa because of positive selection due to falciparum malaria. Nowadays, it is a global health problem because of population migration.

• Fig. 27.1, Changes in haemoglobin tetramers (top panel) and in globin subunits (bottom panel) during human development from embryo to early infancy.

TABLE 27.1

Genotypes and Phenotypes of α-Thalassemias ^a

Number of Functional α-Globin Genes	Disorders or Normal	Genotype	Phenotype
0	Homozygous α ⁰ -thalassemia	(--/--)	Hydrops fetalis
1	Haemoglobin H disease	(--/-α) or (--/α ^T α)	Moderate anaemia, usually not transfusion dependent
2	Homozygous for α ⁺ -thalassemia or heterozygous for α ⁰ -thalassemia	(-α/-α), (α ^T α/α ^T α) or (--/αα)	No clinical problems Low MCV and MCH
3	α ⁺ -Thalassemia	(-α/αα), (α ^T α/αα)	No clinical problems Slightly reduced MCV and MCH
4	Normal	(αα/αα)	Normal MCV and MCH

MCH, Mean corpuscular haemoglobin; MCV, mean corpuscular volume.

a α ⁰ -Thalassemia: deletions of both α-globin genes in cis in the same chromosome (--); α ⁺ -thalassemia: deletion of one of the two α-globin genes (-α), or a nondeletion defect (α ^T α) on one chromosome.

TABLE 27.2

Genotypes and Phenotypes of β-Thalassemias and Related Disorders

Disorder	Genotype	Phenotype
Homozygous β ⁰ -thalassemia or Compound heterozygous for β ⁰ -thalassemia/Hb Lepore or severe β ⁺ -thalassemia	(β ^0/ β ⁰ ) (β ⁰ /Hb Lepore or severe β ⁺ -thalassemia)	Thalassemia major
Compound heterozygous for β ⁰ -thalassemia/β ⁺ -thalassemia or Homozygous β ⁺ -thalassemia or Compound heterozygous for Hb E/β ⁰ or severe β ⁺ -thalassemia or Compound heterozygous for δβ ⁰ -thalassemia/β ⁰ or severe β ⁺ -thalassemia	(β ^0/ β ⁺ ) (β ^+/ β ⁺ ) (Hb E/β ⁰ or β ⁺ ) (δβ ⁰ -thalassemia/β ⁰ or β ⁺ )	Variable: thalassemia intermedia to major depending on type of β ⁺ mutation (mild or severe)
Compound heterozygous for Hb O-Arab/β ⁰ -thalassemia	(Hb O-Arab/β ⁰ -thalassemia)	Severe thalassemia intermedia
Homozygous δβ ⁰ -thalassemia	(δβ ^0/ δβ ⁰ )	Thalassemia intermedia
Compound heterozygous for δβ ⁰ -thalassemia/mild β ⁺ -thalassemia or Compound heterozygous for ααα/β ⁰ or severe β ⁺ -thalassemia	(δβ ⁰ -thalassemia/β ⁺ ) (ααα/β ⁰ or β ⁺ )	Mild thalassemia intermedia
Compound heterozygous for Hb C/β ⁰ or severe β ⁺ -thalassemia	(Hb C/β ⁰ orβ ⁺ -thalassemia)	Variable: β-thalassemia trait to intermedia
Heterozygous for β ⁰ -thalassemia or β ⁺ -thalassemia	(β ^0/ β) or (β ⁺ /β)	Variable: normal to thalassemia trait Low MCV and MCH
Homozygous or heterozygous for HPFH	(HPFH/HPFH) (HPFH/β)	No clinical problems Low MCV and MCH
Homozygous or heterozygous for Hb E	(Hb E/Hb E) (Hb E/β)	No clinical problems Normal or low MCV and MCH
Normal	(β/β)	Normal MCV and MCH

β, Normal β-globin genotype; Hb, haemoglobin; HPFH, hereditary persistence of fetal haemoglobin; MCH, mean corpuscular haemoglobin; MCV, mean corpuscular volume.

Thalassemia is an autosomal recessive disorder. If the couple carry the same (α or β) thalassemia trait, their offspring have a one in four risk for thalassemia major. Prevention programs for severe thalassemia have been implemented in many countries, mostly by prenatal or premarital screening and diagnosis and rarely by preimplantation genetic diagnosis; however, this is not feasible in developing countries. Although the cost-effectiveness of prenatal screening program for β-thalassemia has been demonstrated, there is limited evidence on screening for α-thalassemia.

Thalassemias

α-Thalassemia

In a normal individual, there are four α-globin genes. α-Thalassemia is characterised by a deficiency of α-globin chain synthesis caused by a defect in one or more of the four α-globin genes. Its clinical presentation varies, depending on the number of the defective α-globin genes and the function of the remaining α-globin genes (from zero to three) (see Table 27.1 ).

Two or Three Functional α-Globin Genes

Individuals with α-thalassemia trait are asymptomatic. The mutations are denoted as α ⁰ - or α ⁺ -thalassemia ( Table 27.3 ). In α ⁰ -thalassemia, deletions involve both α-globin genes with or without ζ- globin genes. The gene defect in α ⁺ -thalassemia are mostly deletional such as the 3.7-kb deletion (-α ^3.7 ) or the 4.2-kb deletion (-α ^4.2 ) and less commonly nondeletional such as Hb Quong Sze or Hb Constant Spring.

TABLE 27.3

Gene Deletion or Mutation in and Distribution of α-, β-Thalassemia and δβ ⁰ -Thalassemia

Thalassemia	Gene Deletions or Mutations	Distribution
α ⁺ -Thalassemia	-α ^3.7	Worldwide Common in Africa, Mediterranean countries, the Middle East, the Indian subcontinent and Melanesia
	-α ^4.2	Worldwide Common in Southeast Asia and Pacific regions
	-α ^T	Mostly found in Mediterranean area, Africa and Southeast Asia
α ⁰ -Thalassemia	-- ^SEA	Southeast Asia and South China
	-- ^THAI	Thailand and South China
	-- ^FIL	Philippines
	-(α) ^20.5	Mediterranean countries such as Greece, Cyprus and Turkey
	-- ^MED	Mediterranean countries such as Greece, Cyprus and Turkey
	-- ^SA	Rare in India
	-- ^BRIT	Rare in the United Kingdom
β ⁺ -Thalassemia	β ⁺	Mediterranean countries, Southeast Asia, Africa and United Kingdom
β ⁰ -Thalassemia	β ⁰	South Asia, Indonesia
δβ ⁰ -Thalassemia	δβ ⁰	Mediterranean countries, Vietnam and South China

-(α) ^20.5 , 20.5-kb Deletion involving α2-globin gene and the 5’ end of α1-globin gene; -α ^3.7 , 3.7-kb deletion of α2-globin gene; -α ^4.2 , 4.2-kb deletion of α2-globin gene; -α ^T , other deletion of α2-globin gene; -- ^BRIT , British; --FIL, Filipino; -- MED, Mediterranean; --SA, South African; -- SEA, Southeast Asian; --THAI, Thai.

No Functional α-Globin Genes: Hb Bart Disease or Homozygous α ⁰ -Thalassemia

Because all four α-globin genes are deleted, a fetus affected by homozygous α ⁰ -thalassemia cannot synthesise any α-globin to produce fetal haemoglobin (Hb F [α2γ2]) in utero or Hb A (α2β2) after birth. An affected fetus develops anaemia starting from 8 weeks’ gestation when there is a switch from the ζ to the α gene (see Fig. 27.1 ), with production of the abnormal Hb Bart (γ 4), which does not release oxygen as effectively as the Hb F, and a small amount of Hb Portland (ζ2γ2), resulting in hypoxia, hydrops fetalis, stillbirth or neonatal death. Severe maternal complications, including preeclampsia-like ‘mirror’ syndrome or postpartum haemorrhage, or rarely maternal death, can occur. Long-term survivors after in utero and postnatal transfusion and bone marrow transplant have been reported, some with congenital anomalies, delay in cognitive and motor function, and problems of iron overload. In cases of -- ^FIL /-- ^FIL in which deletion involve both α- and ζ-globin genes, miscarriage may occur before 8 weeks.

One Functional α-Globin Gene: Hb H Disease

In Hb H disease, three of four α-globin genes are defective, and only one α-globin gene is functional. There are two types of Hb H disease: deletional (genotype --/- α ) and nondeletional (genotypes --/α ^T α). The latter type can have a more severe phenotype than the former. In general, patients with Hb H disease can have relatively normal lives and are not transfusion dependent. They have moderate anaemia, splenomegaly and may require transfusions or hospitalisation during stress or infection.

β-Thalassemia

In a normal fetus, there are two β-globin genes. β-Thalassemia is characterised by a deficiency of β-globin chain synthesis caused by a defect of one or both β-globin genes, which results in β-thalassemia trait or homozygous β-thalassemia, respectively.

β-Thalassemia Trait

Individuals with β-thalassemia trait are asymptomatic. Most β-thalassemia mutations are nondeletional. The mutations are denoted as either β ⁺ type, which is associated with a reduction of the expression of the β-globin gene, or β ⁰ type, which is associated with the complete absence of β-globin (see Table 27.3 ).

Of these β ⁺ or β ⁰ -type mutations, the majority are associated with a severe phenotype in homozygotes. Patients with a milder phenotype have an increased amount of β-gene expression or Hb F production.

Homozygous β-Thalassemia

In contrast to Hb Bart disease, a fetus affected by homozygous β-thalassemia will not develop anaemia in utero because of the presence of Hb F (α2γ2). Anaemia will become apparent several months after birth when switching from γ to β and δ genes occurs (see Fig. 27.1 ), and there are no functional β-globin genes to produce normal adult haemoglobin (Hb A [α2β2]).

β-Thalassemia major can be caused by homozygous β ⁰ -thalassemia, compound heterozygosity for β ⁰ -thalassemia/β ⁺ (severe) -thalassemia or homozygous β ⁺ (severe) -thalassemia (see Table 27.2 ). Affected individuals are transfusion dependent, have iron overload from repeated transfusion and may die in the second or third decade of life from cardiac failure, although some may reach 40 years of age in good health, and have children. With the availability of a human leukocyte antigen–matched sibling or relative, bone marrow transplantation can successfully cure this disorder.

β-Thalassemia intermedia can be caused by compound heterozygosity for β ⁰ -thalassemia/β ⁺ (mild) -thalassemia or homozygous β ⁺ (mild) -thalassemia (see Table 27.2 ). The clinical presentation can be variable. In general, affected individuals have a milder clinical condition, present later, receive fewer blood transfusions and have less iron overload than individuals with thalassemia major.

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