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Inherited diseases of haemoglobin haemoglobinopathies are by far the most important.

The structure of human haemoglobin (Hb) changes during development.

By the 12th week 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 chains plus two β chains), Hb A2 has the structure of α2 Ω2, and Hb F, α2 λ2.

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 compound heterozygous state for the sickle cell gene and that for either Hb C (another β chain variant) or β thalassaemia (termed Hb SC disease or sickle cell β thalassaemia).

The sickle cell mutation results in a single amino acid substitution in the β globin chain; heterozygotes have one normal (βA) and one affected β chain (βS) gene and produce about 60% Hb A and 40% Hb S; homozygotes produce mainly Hb S with small amounts of Hb F.

Compound heterozygotes 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.

Pathophysiology

The amino acid substitution in the β globin chain causes red cell sickling during deoxygenation, leading to increased rigidity and aggregation in the microcirculation.

These changes are reflected by a haemolytic anaemia and episodes of tissue infarction.

Geographical distribution

The sickle cell gene is spread widely throughout Africa and in countries with African immigrant populations; some Mediterranean countries; 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.

Patients with sickle cell anaemia have a haemolytic anaemia, with haemoglobin concentration 60-100 g/l and a high reticulocyte count; the blood film shows polychromasia and sickled erythrocytes.

Patients adapt well to their anaemia, and it is the vascular occlusive or sequestration episodes (“crises”) that pose the main threat.

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 appropriate 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 diagnosis is established babies should receive penicillin daily and be immunised 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 a transfusion; there is good evidence now 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 painful 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, this should be only for a short period.

Aplastic crises require urgent blood transfusion.

Splenic sequestration crises require transfusion and, because they may recur, splenectomy is advised.

Sickling variants

Hb SC disease is characterised 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 transfusion.

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 or β thalassaemias, depending on which pair of globin chains is synthesised inefficiently.

Rarer forms affect both β and chain production β 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. Like sickle cell anaemia, it is thought to be common because carriers have been protected 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 completely (β thalassaemia) or partially (β° thalassaemia).

They are inherited like sickle cell anaemia; carrier parents have a one in four chance of having a homozygous child.

The genetics of the thalassaemias is more complicated because normal people have two α globin genes on each of their chromosomes 16.

If both are lost (α° 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.

Impaired α globin production leads to excess λ or β chains that form unstable and physiologically useless tetramers, λ4 (Hb Bart’s) and β4 (Hb H).

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, and have a mean Hb A2 level of about twice normal. Homozygotes, or those who have inherited a different β thalassaemia gene from both parents, usually develop severe anaemia in the first year of life.

This results from a deficiency of β globin chains; excess chains precipitate in the red cell precursors leading to their damage, either in the bone marrow or 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 normal. However, they accumulate iron and may die later from damage to the myocardium, pancreas, or liver. They are also prone to infection and folic acid deficiency.

Milder forms of β thalassaemia (thalassaemia intermedia), although not transfusion dependent, are sometimes associated with similar bone changes, anaemia, leg ulcers, and delayed development.

The α thalassaemias

The Hb Bart’s hydrops fetalis syndrome is characterised 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  thalassaemia or the homozygous state for thalassaemia result in a mild hypochromic anaemia with normal Hb A2 levels.

They can only be distinguished with certainty by DNA analysis in a specialised laboratory.

In addition to the distribution mentioned above, α thalassaemia 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 thalassaemia associated with mental retardation (ATR); one is encoded on chromosome 16 (ATR-16) and the other on the X chromosome (ATRX).

ATR-16 is usually associated with mild mental retardation and is due to loss of the α globin genes together with other genetic material from the end of the short arm of chromosome 16.

ATRX is associated with more severe mental retardation 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 9th and 13th weeks of pregnancy.

If diagnosis is established, the patients should be treated by regular blood transfusion with surveillance for hepatitis C and related infections.

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.

It is now clear that it does not maintain iron balance in approximately 50% of patients and its long term toxicity remains to be evaluated by adequate controlled trials.

It is known to cause neutropenia and transient arthritis.

Current studies are directed at assessing its value in combination with desferrioxamine.

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 vaccinated 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 glutathione 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 kind 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, mainly the same racial groups as are affected by the thalassaemias.

Glucose-6-phosphate dehydrogenase deficiency is sex linked and affects males predominantly.

It causes neonatal jaundice, sensitivity to fava beans (broad 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 a 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.