The Hereditary Anaemias

Hereditary anaemias include disorders of the structure or synthesis of haemoglobin (Hb), deficiencies of enzymes that provide the red cell with energy or protect it from chemical damage and abnormalities of the proteins of the red cell’s membrane. Inherited diseases of haemoglobin (haemoglobinopathies) are by far the most important. The structure of human Hb changes during development (Fig.3.1). By the 12th week of gestation, embryonic haemoglobin is replaced by fetal haemoglobin (Hb F), which is slowly replaced after birth by the adult haemoglobins, Hb A and Hb A2. Each type of haemoglobin consists of two different pairs of peptide chains; Hb A has the structure α2β2 (namely, two α chains plus two β chains), Hb A2 has the structure α 2δ 2 and Hb F, α 2γ2.

The haemoglobinopathies consist of structural haemoglobin variants (the most important of which are the sickling disorders) and thalassaemias (hereditary defects of the synthesis of either the α or β globin chains).

The sickling disorders

Classification and inheritance

The common sickling disorders consist of the homozygous state for the sickle cell gene, that is, sickle cell anaemia (Hb SS), and the

Figure 3.1  Simplified representation of the genetic control of human haemoglobin (Hb). Because α chains are shared by both fetal and adult Hb, mutations of the α globin genes affect Hb production in both fetal and adult life; diseases that are due to defective β globin production are only manifest after birth when Hb A replaces Hb F.

compound heterozygous state for the sickle cell gene and for either Hb C (another β chain variant) or β thalassaemia (termed Hb SC disease or sickle cell β thalassaemia) (Box 3.1). The sickle cell muta- tion results in a single amino acid substitution in the β globin chain; heterozygotes have one normal (βA) and one affected (βS) β chain gene and produce about 60% Hb A and 40% Hb S; homozygotes produce mainly Hb S with small amounts of Hb F. Compound het- erozygotes for Hb S and Hb C produce almost equal amounts of each variant, whereas those who inherit the sickle cell gene from one parent and β thalassaemia from the other make predominantly sickle haemoglobin (Fig. 3.2). 

Pathophysiology 

The amino acid substitution in the β globin chain causes red cell sickling during deoxygenation, leading to increased rigidity and ag- gregation in the microcirculation. These changes are reflected by a haemolytic anaemia and episodes of tissue infarction (Fig. 3.3).

Figure 3.2  Haemoglobin  electrophoresis showing (1) normal, (2) newborn, (3) Hb C trait (A-C), (4) Hb SC disease (SC), (5) sickle cell disease (SS), (6) sickle cell trait (A-S), (7) newborn, (8) normal.

Figure 3.3  Peripheral blood film from patient  with sickle cell anaemia showing sickled erythrocytes.

Geographical distribution

The sickle cell gene is spread widely throughout Africa and in countries with African immigrant populations; some Mediterranean coun- tries, the Middle East and parts of India. Screening should not be restricted to people of African origin.

Clinical features

Sickle cell carriers are not anaemic and have no clinical abnormalities (Box 3.2). Patients with sickle cell anaemia have a haemolytic anaemia, with a low haemoglobin concentration and a high reticulo- cyte count; the blood film shows polychromasia and sickled eryth- rocytes (Fig. 3.3, Box 3.3).

Patients adapt well to their anaemia and it is the vascular occlusive or sequestration episodes (‘crises’) that pose the main threat (Box 3.4). Crises take several forms. The commonest, called the painful crisis, is associated with widespread bone pain and is usually self-limiting. More serious and life-threatening crises include the sequestration of red cells into the lung or spleen, strokes, or red cell aplasia associated with parvovirus infections.

Diagnosis

Sickle cell anaemia should be suspected in any patient of an appro-

priate racial group with a haemolytic anaemia. It can be confirmed by a sickle cell test, although this does not distinguish between heterozygotes and homozygotes. A definitive diagnosis requires haemoglobin electrophoresis and the demonstration of the sickle cell trait in both parents.

Prevention and treatment

Pregnant women in at-risk racial groups should be screened in early pregnancy and, if the woman and her partner are carriers, should be offered either prenatal or neonatal diagnosis. As soon as the diag- nosis is established, babies should receive penicillin daily and be im- munized against Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis. Parents should be warned to seek medical advice on any suspicion of infection. Painful crises should be managed with adequate analgesics, hydration and oxygen. The patient should be observed carefully for a source of infection and a drop in haemoglobin concentration. Pulmonary sequestration crises require urgent exchange transfusion together with oxygen therapy. Strokes should be treated with an exchange transfusion; there is now good evidence that they can be prevented by regular surveillance of cerebral blood flow by Doppler examination and prophylactic transfusion. There is also good evidence that the frequency of pain- ful crises can be reduced by maintaining patients on hydroxyurea, although, because of the uncertainty about the long-term effects of this form of therapy, it should be restricted to adults or, if it is used in children, should be used only for a short period. Aplastic crises require urgent blood transfusion. Splenic sequestration crises require transfusion and, because they may recur, splenectomy is advised (Box 3.5).

Sickling variants

Hb SC disease is characterized by a mild anaemia and fewer crises. Important microvascular complications, however, include retinal damage and blindness, aseptic necrosis of the femoral heads and recurrent haematuria. The disease is occasionally complicated by pulmonary embolic disease, particularly during and after pregnancy; these episodes should be treated by immediate exchange trans- fusion. Patients with Hb SC should have annual ophthalmological surveillance; the retinal vessel proliferation can be controlled with

laser treatment. The management of the symptomatic forms of sickle cell β thalassaemia is similar to that of sickle cell anaemia.

The thalassaemias

Classification

The thalassaemias are classified as α or β thalassaemias, depending on which pair of globin chains is synthesized inefficiently. Rarer forms affect both β and δ chain production: δβ thalassaemias.

Distribution

The disease is broadly distributed throughout parts of Africa, the Mediterranean region, the Middle East, the Indian subcontinent and South East Asia, and it occurs sporadically in all racial groups (Fig.3.4). Like sickle cell anaemia, it is thought to be common because the mutation protects carriers against malaria.

Inheritance

The β thalassaemias result from over 150 different mutations of the β globin genes, which reduce the output of β globin chains, either

Figure 3.4  Distribution of the thalassaemias

(red area).

Figure 3.5  Inheritance of Hb disease (open boxes represent normal α globin genes and red boxes deleted  α globin genes).

Figure 3.6  Pathophysiology of α thalassaemia.

completely (β˚ thalassaemia) or partially (β+ thalassaemia). They are inherited in the same way as sickle cell anaemia; carrier parents have a one in four chance of having a homozygous child. The genetics of the α thalassaemias is more complicated because normal people have two α globin genes on each of their chromosomes 16. If both are lost (αº thalassaemia) no α globin chains are made, whereas if only one of the pair is lost (α+ thalassaemia) the output of α globin chains is reduced (Fig. 3.5). Impaired α globin production leads to excess γ or β chains that form unstable and physiologically useless tetramers: γ4 (Hb Bart’s) and β4 (Hb H) (Fig. 3.6). The homozygous state for α˚ thalassaemia results in the Hb Bart’s hydrops syndrome, whereas the inheritance of α˚ and α+ thalassaemia produces Hb H disease. 

The β thalassaemias Heterozygotes for β thalassaemia are asymptomatic, have hypochromic microcytic red cells with a low mean cell haemoglobin and mean cell volume (Fig. 3.7), and have a mean Hb A2 level of about twice that of normal (Box 3.6). Homozygotes, or those who have inherited a different β thalassaemia gene from both parents, usually develop severe anaemia in the first year of life (Box 3.7). This results from a deficiency of β globin chains; excess α chains precipitate in the red cell precursors leading to their damage, either in the bone marrow or

Figure 3.7  Peripheral blood film in homozygous β thalassaemia showing pronounced hypochromia  and anisocytosis with nucleated red blood cells.

the peripheral blood. Hypertrophy of the ineffective bone marrow leads to skeletal changes, and there is variable hepatosplenomegaly. The Hb F level is always raised. If these children are transfused, the marrow is ‘switched off ’, and growth and development may be nor- mal. However, they accumulate iron and may die later from damage to the myocardium, pancreas, or liver (Fig. 3.8). They are also prone to infection and folic acid deficiency.

Milder forms of β thalassaemia (thalassaemia intermedia), although not transfusion dependent, are often associated with similar bone changes, anaemia, leg ulcers and delayed development. The most important form of β thalassaemia intermedia is Hb E β thalassaemia, which results from the inheritance of Hb E and a β thalassaemia

Figure 3.8  Liver biopsy from patient  with β thalassaemia showing pronounced iron accumulation

gene. This condition is the commonest form of severe thalassaemia in many parts of Asia and is associated with a remarkably diverse clinical course; some patients are transfusion dependent while others may remain asymptomatic. 

The α thalassaemias 

The Hb Bart’s hydrops fetalis syndrome is characterized by the stillbirth of a severely oedematous (hydropic) fetus in the second half of pregnancy. Hb H disease is associated with a moderately severe haemolytic anaemia. The carrier states for αº thalassaemi a and the homozygous state for α+ thalassaemia result in a mild hypochromic anaemia with normal Hb A2 levels (Box 3.8). They can only be distinguished with certainty by DNA analysis in a specialized laboratory. In addition to the distribution mentioned above, α tha- lassaemia is also seen in European populations in association with mental retardation; the molecular pathology is quite different to the common inherited forms of the condition. There are two major forms of α thalassaemia associated with mental retardation (ATR); one is encoded on chromosome 16 (ATR-16) and the other on the X chromosome (ATR-X). ATR-16 is usually associated with mild mental retardation and is due to loss of the β globin genes together with other genetic material from the end of the short arm of chromosome 16. ATR-X is associated with more severe mental retarda- tion and a variety of skeletal deformities, and is encoded by a gene on the X chromosome, which is expressed widely in different tissues during different stages of development. These conditions should be suspected in any infant or child with retarded development who has the haematological picture of a mild α thalassaemia trait. 

Prevention and treatment 

As β thalassaemia is easily identified in heterozygotes, pregnant women of appropriate racial groups should be screened; if a woman is found to be a carrier, her partner should be tested and the couple counselled. Prenatal diagnosis by chorionic villus sampling can be carried out between the ninth and 13th weeks of pregnancy (Box 3.9). Babies with β thalassaemia major should be observed very care- fully regarding growth, activity and steady-state haemoglobin level.

When it is certain that they require regular transfusion, they should be given washed red cell transfusions at monthly intervals; it is vital that the blood is screened for human immunodeficiency virus/ac- quired immunodeficiency syndrome, hepatitis B and C viruses and, in some countries, malaria.

To prevent iron overload, overnight infusions of desferrioxamine together with vitamin C should be started, and the patient’s serum ferritin, or better, hepatic iron concentrations, should be monitored; complications of desferrioxamine include infections with Yersinia spp., retinal and acoustic nerve damage and reduction in growth associated with calcification of the vertebral discs.

The place of the oral chelating agent deferiprone is still under evaluation. Although it appears not to maintain iron balance in up to 50% of patients, and it causes neutropenia and variably severe arthritis, recent work suggests that it may be more effective in removing iron from the heart than desferrioxamine; this observation requires confirmation in prospective studies. Another recently de- veloped oral chelating agent, Exjade ® (ICL670), is still under investigation; preliminary studies suggest that it may have comparable activity to desferrioxamine in maintaining iron balance and that it is relatively non-toxic, although further studies are required to confirm that it does not have a deleterious effect on renal function. Bone marrow transplantation, if appropriate HLA-DR-matched siblings are available, may carry a good prognosis if carried out early in life. Treatment with agents designed to raise the production of Hb F is still at the experimental stage.

In β thalassaemia and Hb H disease, progressive splenomegaly or increasing blood requirements, or both, indicate that splenectomy may be beneficial. Patients who undergo splenectomy should be vac-cinated against S. pneumoniae, H. influenzae and N. meningitidis preoperatively, and should receive a maintenance dose of oral penicillin indefinitely.

Red cell enzyme defects

Red cells have two main metabolic pathways, one burning glucose anaerobically to produce energy, the other generating reduced gluta- thione to protect against injurious oxidants. Many inherited enzyme defects have been described. Some of those of the energy pathway, for example, pyruvate kinase deficiency, cause haemolytic anaemia; any child with this type of anaemia from birth should be referred to a centre capable of analysing the major red cell enzymes.

Glucose-6-phosphate dehydrogenase deficiency (G6PD) involves the protective pathway. It affects millions of people worldwide, main- ly the same racial groups as are affected by the thalassaemias. G6PD deficiency is sex linked and affects predominantly males (Box 3.10). It causes neonatal jaundice, sensitivity to broad (fava) beans and haemolytic responses to oxidant drugs.

Red cell membrane defects

The red cell membrane is a complex sandwich of proteins that are required to maintain the integrity of the cell. There are many inherited defects of the membrane proteins, some of which cause haemolytic anaemia. Hereditary spherocytosis is due to a structural change that makes the cells more leaky. It is particularly important to identify this disease because it can be ‘cured’ by splenectomy. There are many rare inherited varieties of elliptical or oval red cells, some associated

with chronic haemolysis and response to splenectomy. A child with chronic haemolytic anaemia with abnormally shaped red cells should always be referred for expert advice.

Other hereditary anaemias

Other anaemias with an important inherited component include Fanconi’s anaemia (hypoplastic anaemia with skeletal deformities), Blackfan–Diamond anaemia (red cell aplasia) and several forms of congenital dyserythropoietic anaemia.