Clinical findings

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Most severe forms of P-thalassaemia present within the first year of life with failure to thrive, poor feeding, intermittent bouts of infection and general malaise; the infant is pale, and in many cases splenomegaly is already established. There are no other specific clinical signs and the diagnosis depends on the haemato-logical changes outlined below. If the infant receives regular blood transfusion, early development is normal and further symptoms do not occur until puberty, when the effects of iron loading start to appear. If, on the other hand, the infant is not adequately transfused, the typical clinical picture of P-thalassaemia major develops.

In the well-transfused child, early growth and development are normal and splenomegaly is minimal. However, without adequate iron chelation therapy, there is a gradual accumulation of iron and the effects of tissue siderosis start to appear by the end of the first decade. The adolescent growth spurt fails to occur and hepatic, endocrine and cardiac complications of iron overloading produce a variety of complications, including diabetes, hypoparathyroidism, adrenal insufficiency and progressive liver failure. Secondary sexual development is delayed, or does not occur at all. The short stature and lack of sexual development may lead to serious psychological problems. By far the commonest cause of death, which usually occurs towards the end of the second or early in the third decade, is progressive cardiac damage. Ultimately, these patients die either in protracted cardiac failure or suddenly due to an acute arrhythmia, often precipitated by infection.

The clinical picture in children who are inadequately transfused is quite different. Early childhood is interspersed with a series of distressing complications and the rates of growth and development are retarded. There is progressive splenomegaly, and hypersplenism may cause a worsening of the anaemia, sometimes associated with thrombocytopenia and a bleeding aa/aa - -/aa

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Inclusion bodies Ineffective erythropoiesis haemolysis

Anaemia

Bone disease

Iron loading

Jaundice Infection

VDR OR COL

UGT1A1

Co-selection HLA-DR TNF-a ICAM-1

Figure 6.5 The modification of the P-thalassaemia phenotype. The different levels of genetic modification are shown; primary modifiers involve different P-thalassaemia alleles, secondary modifiers involve the reduction of globin chain imbalance due to either increased HbF production or the co-inheritance of a-thalassaemia, and the tertiary modifiers affect the different complications of the disease. UGT1A1, UDP glucuronsyltransferase; VDR, vitamin D receptor; OR, oestrogen receptor; Col, collagen genes; TNF, tumour necrosis factor; ICAM1, intercellular adhesion molecule 1.

Figure 6.6 The skull in P-thalassaemia.

formed teeth and malocclusion, and inadequate drainage of the sinuses and middle ear may lead to chronic sinus infection and deafness. If these children survive to puberty, they develop the same complications of iron loading as the well-transfused patients. In this case, iron accumulation results from an increased rate of gastrointestinal absorption as well as the inadequate transfusion regimen.

Children who are adequately transfused and chelated may grow and develop normally although, presumably reflecting the extreme sensitivity of the endocrine system to even mild iron overload, there may still be problems with growth, sexual maturation and osteoporosis. Regardless of how they are managed they are prone to blood-borne infection, notably hepatitis B and C, HIV and malaria.

tendency. Because of bone marrow expansion, there may be deformities of the skull with marked bossing and overgrowth of the zygomata, giving rise to the classical 'mongoloid facies' of P-thalassaemia. These signs are associated with radiological changes, which include a lacy, trabecular pattern of the long bones and phalanges and a typical 'hair on end' appearance of the skull (Figure 6.6).

These bone changes may be accompanied by recurrent fractures. There is increased proneness to infection that may cause a catastrophic drop in the haemoglobin level. Because of the massive marrow expansion resulting from the chronic anaemia, these children are hypermetabolic and develop intermittent fevers and fail to thrive. They have increased requirements for folic acid and may become acutely folate depleted with worsening of their anaemia. Because of the increased turnover of red cell precursors, hyperuricaemia and secondary gout occur occasionally. There is a bleeding tendency which, although partly due to thrombocytopenia secondary to hypersplenism, may also be exacerbated by liver damage. Because of the deformities of the skull, there may be distressing dental complications, with poorly

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