Hb-Barts hydrops syndrome (– –/– –)

Here deletion of all four genes leads to complete absence of α-chain synthesis. As the α-globin chain is needed for fetal haemoglobin (HbF) as well as adult haemoglobin (HbA) (see p. 5) the disorder is incompatible with life and death occurs in utero (hydrops fetalis).

HbH disease (–α/– –)

This disorder arises from deletion of three of the four α-globin genes and is found most commonly in South-East Asia. The clinical features are variable but there is often a moderate chronic haemolytic anaemia (Hb 70–110 g/L) with splenomegaly and sometimes hepatomegaly. Severe bone changes and growth retardation are unusual. The blood film shows hypochromic microcytic red cells with poikilocytosis, polychromasia and target cells. The HbH molecule is formed of unstable tetramers of unpaired β chains (β₄). It is best detected by electrophoresis but may be demonstrated as red cell inclusion bodies in reticulocyte preparations.

α-Thalassaemia traits

Deletion of a single α-globin chain leads only to a slight lowering of red cell mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) and even deletion of two genes usually only minimally lowers the haemoglobin with a raised red cell count and hypochromia and microcytosis. These carrier states can be difficult to identify in the routine laboratory as haemoglobin electrophoresis is normal. Occasional HbH bodies may be detected in reticulocyte preparations. Definitive diagnosis requires DNA analysis.

β-Thalassaemia major

The characteristic severe anaemia (Hb less than 70 g/L) is caused by α-chain excess leading to ineffective erythropoiesis and haemolysis. Anaemia first becomes apparent at 3–6 months when production of HbF declines. The child fails to thrive and develops hepatosplenomegaly. Compensatory expansion of the marrow space causes the typical facies with skull bossing and maxillary enlargement (Fig 16.1a). The ‘hair-on-end’ radiological appearance of the skull (Fig 16.1b) is due to expansion of bone marrow into cortical bone. If left untreated further complications can include repeated infections, bone fractures and leg ulcers. Red cell membrane abnormalities contribute to hypercoagulability.

Laboratory testing should precede blood transfusion. There is a severe hypochromic microcytic anaemia with a characteristic blood film (Fig 16.2) and Hb electrophoresis demonstrates absence or near absence of HbA with small amounts of HbA₂ and the remainder HbF (Fig 16.3).

With intense supportive therapy, increasing numbers of patients in the developed world survive into adulthood. Blood transfusion remains the mainstay of management. Raising the haemoglobin concentration both reduces tissue hypoxia and suppresses endogenous haematopoiesis which is largely ineffective. There is improved growth and development and reduced hepatosplenomegaly. Transfusion is generally given to maintain a haemoglobin level of at least 90–100 g/L. Splenectomy can reduce the transfusion frequency. With such regular transfusion iron chelation is necessary to minimise iron overload. Without chelation, accumulation of iron damages the liver, endocrine organs and heart with death in the second or third decades. The most commonly used regimen is subcutaneous desferrioxamine given for 5–7 days per week. Compliance may be problematic (especially in teenagers) but where good there is a considerably improved life expectancy. Oral iron chelators (e.g. deferiprone, deferasirox) are emerging as an acceptable alternative. Endocrine disturbances related to iron overload will require appropriate therapy.

Allogeneic stem cell transplantation is a serious option. In ‘best risk’ patients the probability of survival exceeds 90%. Experimental therapies include drugs designed to stimulate fetal haemoglobin production (e.g. erythropoietin, hydroxycarbamide) and gene therapy (see p. 103).

Thalassaemia intermedia

Thalassaemia intermedia is a clinical syndrome which may result from a variety of genetic abnormalities (Table 16.2). The clinical features are less severe than in β-thalassaemia major as the α/β-globin chain imbalance is less pronounced. Patients usually present later than is the case for β-thalassaemia major (often at 2–4 years), and have relatively high haemoglobin levels (80–100 g/L), moderate bone changes and normal growth. Transfusion may be required but requirements are less than in β-thalassaemia major.

β-Thalassaemia trait (minor)

Heterozygotes for β⁰ or β⁺ are usually asymptomatic with hypochromic microcytic red cells and slightly reduced haemoglobin levels. The red cell count is elevated. The key diagnostic feature is a raised HbA₂ level (4–7%). The disorder may be confused with iron deficiency leading to unnecessary investigations. If both parents have β-thalassaemia trait there is a 25% chance of a child having β-thalassaemia major.