Thalassaemia

Key Information

Appropriate Tests

An inherited disorder characterised by reduced globin chain synthesis and secondary imbalance of globin chains.

Thalassaemias are classified according to the globin gene affected, and also according to the phenotype.

Alpha and beta thalassaemia have potential clinical significance and the severity of disease varies greatly – from a completely asymptomatic condition to disease incompatible with life.

Full blood count, Blood film, red cell indices (especially MCV ), Haemoglobin electrophoresis, HbA2, HbF, HbH inclusions, Iron studies, directed molecular testing of relevant genes.

Testing may be indicated based on abnormal results on Full blood count or antenatal screening in 'at risk' couples. The diagnosis of thalassaemic disorders usually requires a combination of techniques and involves evaluation of red cell indices and blood film, quantitation of HbA2 and HbF, detection of variant haemoglobin and DNA analysis when indicated.

It is important to identify and treat any associated iron deficiency, as this may lead to reduced HbA2 and therefore lead to a false normal HbA2 in patients with beta-thalassaemia trait. However, in pregnant women testing should not be delayed whilst treating iron deficiency, as this will delay the identification of 'at-risk' carrier couples.

See also Haemoglobinopathy

Beta thalassaemia

Normal individuals have one paternal and one maternal globin gene (ß /ß). In beta thalassaemic states one (heterozygous) or both (homozygous) beta globin genes are abnormal.

Heterozygous (beta thalassaemia trait)

Spouse/partner should also be tested where clinically indicated to allow for consideration of risk of clinically severe phenotype in their offspring.

May also be referred to as beta thalassaemia minor, and is usually clinically asymptomatic. During times of haematopoietic stress (eg, pregnancy, intercurrent illness), the patient may become anaemic.

The Full blood count usually shows a microcytosis and may show mild microcytic anaemia. Diagnosis rests on demonstration of increased HbA2 percentage.

Problems with diagnosis: beta thalassaemia cannot be diagnosed from HbA2 in neonates; there are beta gene mutations that do not cause an increase in HbA2 ('silent beta thalassaemia trait') and can only be diagnosed on molecular genetic testing; iron deficiency can lower HbA2 percentage and lead to HbA2 within normal range in patients with mild beta thalassaemia trait - testing should be deferred until correction of iron deficiency except in pregnancy, when the diagnosis cannot be delayed; coinheritance with other abnormalities of globin chain synthesis; other clinical conditions causing macrocytosis may in some cases increase the MCV in these patients into the normal range.

Spouse/partner should also be tested.

Homozygous or compound heterozygous (thalassaemia major)

Beta thalassaemia major refers to patients who are homozygous or compound heterozygous for beta thalassaemia.

Disease severity varies; some patients in which the thalassaemic mutation reduces but does not eliminate ß globin production (beta +), or patients with high HbF, may have a milder phenotype, and not be transfusion dependent ('thalassaemia intermedia', a clinical diagnosis).

Iron overload occurs due to increased iron absorption and secondary to transfusion therapy if there is inadequate iron chelation. Iron deposition can result in liver dysfunction, cardiac disease and endocrine abnormalities.

Double heterozygous, ie, multiple haemoglobinopathies (thalassaemia or intermedia)

Spouse/partner should also be tested.

May have features of thalassaemia intermedia or thalassaemia major.

Alpha thalassaemia

The alpha thalassaemias are a group of conditions resulting from a reduced rate of synthesis of alpha-globin. Some of the clinical features are due to lack of alpha-globin chains, and others are due to damage to red cells by excess non-alpha chains. The clinical syndromes vary greatly from completely asymptomatic to Hb Bart's hydrops fetalis, a condition incompatible with life.

Normal individuals have four globin genes, inherited as a block of two alpha genes from both parents. When both alpha-globin genes are deleted or transcriptionally completely inactive, the designation α0is used. When there is some residual alpha-globin chain production, the designation α+ is used. Alpha thalassaemia can be divided into deletional and non-deletional thalassaemias.

The diagnosis of alpha thalassaemia trait is usually suspected when there is microcytosis not explained by beta- or other thalassemia (based on Hb electrophoresis and HPLC) or iron deficiency. Occasionally HbH inclusions may be detected, however this is not a reliable diagnostic test. Definitive diagnosis requires DNA analysis (see molecular genetic testing).

Spouse/partner should also be tested. 

Heterozygous α+ (α-/αα)

This is usually associated with a normal phenotype or very mild microcytosis.

Heterozygous α0 (--/αα)

This usually has a thalassaemia trait phenotype (mild microcytic anaemia).

Homozygous α+ (α-/α-)

This usually has a thalassaemia trait phenotype (mild microcytic anaemia).

Haemoglobin H disease (--/-α)

Typically the haemoglobin is ~80 g/L with a severe microcytosis. Patients are usually well and transfusion independent, but may develop iron overload.

Homozygous α0 (--/--)

This is not compatible with life, and typically results in early miscarriage or third trimester hydropic fetus and fetal death.

Hydrops fetalis

See Hb Barts hydrops fetalis syndrome under Hydrops fetalis.

Prenatal diagnosis

See Molecular genetics - genetic disorders.