Beta-thalassaemia

Family history and ancestry is key to starting the diagnosis of beta-thalassaemia. Further testing is driven by the presence of signs and symptoms, to avoid unnecessary testing in beta-thalassaemia trait.

Beta-thalassaemia major

If antenatal diagnosis has been made, newborn screening haemoglobin analysis may confirm the diagnosis with a complete absence of haemoglobin A (Hb A). Some Hb A may be present at birth but, as the infant becomes more anaemic, there is persistence of fetal haemoglobin (Hb F) and the Hb A does not rise. The infant should be referred to a haematologist, and therapy begun under specialty care.

If antenatal diagnosis has not been made, clinical manifestations may become apparent by 4 to 5 months of age as the haemoglobin level continues to descend below the physiological nadir and the child becomes progressively pale, with skeletal changes (e.g., large head with frontal and parietal bossing, chipmunk facies), misaligned teeth, and hepatosplenomegaly. There may be failure to thrive (low weight and/or height). Jaundice may occur; this is usually mild. Chronic elevation of bilirubin may present with features associated with gallstones. Lethargy is highly suggestive of moderate or severe anaemia.The ethnic background may be a clue, and a detailed interview with the parents may elicit a history within the family of beta-thalassaemia, or iron-refractory or undiagnosed anaemia. The infant should be referred to a haematologist at this time.

The initial complete blood count reveals moderate to severe microcytic anaemia, with normal to elevated leukocyte and platelet counts, and a peripheral smear with microcytic red cells, tear drops, microspherocytes, target cells, and some fragments. Haemoglobin analysis reveals minimal to no Hb A and elevated Hb F and HbA2 levels.

Other initial tests may include: LFTs, skull and long-bone x-ray, and abdominal ultrasound. These elements in the work-up make the diagnosis, and although genetic testing for specific mutations may confirm the diagnosis, it is not necessary. HLA typing may be ordered by the haematologist if stem cell transplantation is a consideration.

Beta-thalassaemia intermedia

If antenatal diagnosis has been made, newborn screening haemoglobin analysis will generally reveal the presence of some Hb A. If the child is a compound heterozygote for some other haemoglobinopathy such as haemoglobin E, this will be evident on the newborn screen. The child will manifest pallor, hepatosplenomegaly, and skeletal changes, depending on the severity of the mutation.

If antenatal diagnosis has not been made, presentation is in childhood with pallor, skeletal changes including chipmunk facies and frontal and parietal bossing, misaligned teeth, and some abdominal distension because of the hepatosplenomegaly. Lethargy is highly suggestive of moderate or severe anaemia. There may be failure to thrive (low weight and/or height). Jaundice may occur. Chronic elevation of bilirubin may present with features associated with gallstones. The ethnic background may be a clue, and a detailed interview with the parents may elicit a family history of beta-thalassaemia, or iron-refractory or undiagnosed anaemia in relatives. The degree of anaemia affects the severity of the clinical manifestations and the age at which the diagnosis is made, but it is generally in the first decade of life.

As in beta-thalassaemia major, the complete blood count reveals moderate to severe microcytic anaemia, with normal to elevated leukocyte and platelet counts, and a peripheral smear with microcytic red cells, tear drops, microspherocytes, target cells, some fragments, and a large number of nucleated red cells. Haemoglobin analysis reveals decreased amounts of Hb A and elevated Hb F and HbA2 levels, and may also show the presence of Hb E if the child is a compound heterozygote.

Other initial tests may include: LFTs (there may be mild to moderate hyperbilirubinaemia, most of it unconjugated), skull and long-bone x-ray, and abdominal ultrasound. Genetic testing may be helpful to predict the severity of the disorder. HLA typing may be ordered by the haematologist if stem cell transplantation is a consideration.

Beta-thalassaemia trait

Antenatal diagnosis may have been made in situations where both parents also have the trait. In this situation, the newborn screen is normal. It is important to keep the diagnosis in mind to avoid additional testing and possibly unnecessary therapy for differential diagnoses such as iron deficiency anaemia in childhood or later.

Most people with beta-thalassaemia trait are asymptomatic and do not have any abnormal physical findings, with the exception of possible mild pallor. The ethnic background and family history may provide clues to the diagnosis.

FBC reveals a mild microcytic anaemia with a near-normal red cell count, a normal red cell distribution width (RDW), and normal leukocyte and platelet counts. Haemoglobin analysis shows mostly Hb A, but HbA2 and Hb F levels are elevated. These tests and any history are usually sufficient to make the diagnosis of this condition.

Genetic testing is not necessary at this time, but may be necessary if the person is planning a family with a partner who also has the trait, or if there is a high suspicion that the partner is a silent carrier.