Paediatrics: Thalassaemia

Thalassaemia

A inherited defect in synthesis of one or more globin chains (globin chain linked to haem group = Hb) resulting in imbalanced globin chain produc-tion l ineffective erythropoiesis l precipitation of excess chains l hae-molysis l variable severity anaemia.

·  At birth the major Hb is HbF (α₂γ₂). By the end of the first year of life and into adulthood the major Hb is HbA (α₂β₂), 72. 5% is HbA₂ (α₂δ₂), and only 1–2% is HbF.

·  HbA (α₂β₂) is comprised of two A globin chains that are encoded by two A-globin genes on each chomosome 16 (i.e. each cell has 4 A-globin genes), designated as (αα/αα).

·  The two β globin chains are encoded by only one β-globin gene on each chromosome 11, designated (β/β).

·  HbF has 2 α globin chains combined with 2 γ (αα/γγ). HbA₂ has 2 α chains combined with 2 δ chains (ααδ).

·  There are various forms of thalassaemia, e.g. β thalassaemia (β chains are not produced), A thalassaemia, δ-β thalassaemia.

·  Thalassaemia genes can be null mutants, which make no globin chains, e.g. β^o or α^o, or can make minimal amounts of globin chains, e.g. β⁺, or α⁺.

·  Thalassaemia major describes the homozygous disease state, e.g. (β^o/β^o)

·  Thalassaemia minor (also called thalassaemia trait) describes carriers (heterozygotes) of either β^o or β⁺ genes or α^o or α⁺ genes.

·  Thalassaemia intermedia describes the spectrum of phenotypes between major and minor (i.e. 3 α gene deletion causes HbH disease, or a β⁺ mutation with another β⁺ mutation.

The severity of anaemia and clinical picture are related to the number and nature of gene mutation and deletions and consequent imbalanced globin chain production. Thalassaemia is common in malaria-affected regions of the world (the trait is probably protective), i.e. parts of Africa, Mediterranean, Middle East, India, and Asia.

α-thalassaemia

·  Silent α-thalassaemia (αα/α−): one α gene deletion. Asymptomatic.

·  α-thalassaemia trait (αα/−−) or  (α−/α−): Two α gene deletion.

Asymptomatic with hypochromic microcytic picture (Hb may be d, MCV d, MCH d). May mimic iron deficiency, if RBC >5.0 x 10¹²/L with microcytic, hypochromic film, then thalassaemia trait more likely.

·  Hb H disease (α−/−−): Three α gene deletion or equivalent. Variable chronic anaemia with mild hepatosplenomegaly and jaundice. Hypochromic anaemia with target cells and reticulocytes i. HbH inclusions (tetramers of B globin) are seen on special staining. Folic acid supplements required, and occasionally transfusions. Splenectomy may be beneficial.

·  Hb Bart’s hydrops fetalis (−−/−−). Four α gene deletion. Causes hydrops fetalis leading to stillbirth or early neonatal death. Hb analysis shows mainly Hb Bart’s (G4). Most often seen in South-East Asia where frequency of (αα/−−) carriers is high.

β-thalassaemia

This disorder is not obvious until γ chain production falls off at around 6mths of age and HbF (αα/γγ) levels fall.

B thalassaemia trait

·(β^o/β) or (β⁺/β).

·Asymptomatic with mild Hb d, MCV d, MCH d.

·HbA₂ characteristically ‘rise’on Hb electrophoresis to > 3.5%.

·No treatment required, but important to detect for genetic counselling purposes, especially if partner also has haemoglobinopathy.

B thalassaemia major

Presentation

·Presents in first year to 18mths as HbF drops, but no Hb A is made leading to anaemia.

·Severe anaemia (3–9g/dL); markedly ‘fall’ MCV and MCH, ‘rise’reticulocytes, target cells, and nucleated RBCs.

·Secondary growth and development failure.

·Extramedullary haematopoiesis causes skeletal deformity (frontal bossing of skull, maxillary swelling) and hepatosplenomegaly in older children who are not adequately transfused.

·Hb electrophoresis shows mainly HbF, but no HbA.

Management

·Regular transfusions (every 3–4wks) to maintain Hb level that suppresses extramedullary haematopoiesis and sustains growth and development.

·Iron overload is major problem, with haemosiderosis affecting the heart, liver, endocrine organs, and pancreas.

·Chelation of iron starts when ferritin level >1000micrograms/L (usually following 10–20 transfusions). Desferrioxamine by SC infusion 5–7 nights per week. Side-effects include: cataracts, hearing loss, Yersinia gut infections. Alternatively, in children over 6yrs give desferiserox (a new oral iron chelator). Start at dose of 20mg/kg/day and monitor renal function.

·Splenectomy may help if massive splenomegaly or increased transfusion requirements.

·Bone marrow transplantation is the only cure and is usually successful when carried out as a planned procedure in a unit that specializes in the procedure, and in well chelated patients with no end organ damage. The procedure carries significant risks.

Thalassaemia intermedia

Has a variable phenotype depending on the genotype from asymptomatic to a moderately severe anaemia, similar to thalassaemia major, that may require intermittent transfusions. This disorder is usually due to co-inheritance of an ameliorating condition, e.g. triplicated α globin chains, and HbF (hereditary persistence of fetal Hb), A thalassaemia trait.