Beta-thalassaemia major and minor

Overview

The thalassaemias are inherited disorders in which globin chain production is reduced or absent. In beta-thalassaemia the defect is in the beta chain. It is one of the commonest serious single-gene disorders in Pakistan and the region, and families with an affected child often have consanguineous parents.

Thalassaemia major is a lifelong, transfusion-dependent anaemia; thalassaemia minor (trait) is a harmless carrier state that matters mainly because it mimics iron deficiency and because two carriers can have an affected child.

Genetics

• Adult haemoglobin is HbA (α2β2); fetal haemoglobin is HbF (α2γ2); a minor adult form is HbA2 (α2δ2).
• The beta globin gene is on chromosome 11; each person has two copies.
• Inheritance is autosomal recessive.
• β0 means no beta chain from that gene; β+ means a reduced amount.

Risk to children of two carriers

In each pregnancy: 25% thalassaemia major, 50% carrier, 25% unaffected.

Pathophysiology

1. Beta chain production is low or absent, so alpha chains are left over.
2. The excess alpha chains precipitate inside developing red cells in the marrow, which are destroyed there (ineffective erythropoiesis) and in the spleen (haemolysis).
3. Severe anaemia drives very high erythropoietin, so the marrow expands enormously: bone deformity, thin cortices, fractures and extramedullary haematopoiesis in liver and spleen.
4. The body responds by making more gamma and delta chains, so HbF and HbA2 rise. HbF holds oxygen tightly and delivers it poorly.
5. Increased gut iron absorption plus transfusions lead to iron overload.

Clinical features

Thalassaemia minor

• Normal growth and development; usually no symptoms.
• Mild microcytic anaemia (haemoglobin around 10 g/dL or normal).
• Often discovered on a routine count or when iron does not help.

Thalassaemia intermedia

• Presents later, often by 2-4 years, with moderate anaemia.
• Splenomegaly, growth failure, jaundice and facial changes can develop; iron overload is still a risk even without many transfusions.

Thalassaemia major

• Symptoms by about 3-12 months: pallor, poor feeding, irritability, failure to thrive.
• Severe anaemia with a slight icteric tinge.
• Massive hepatosplenomegaly and a protuberant abdomen.
• Thalassaemic (chipmunk) facies: frontal bossing, prominent cheeks and jaw, depressed nasal bridge.
• Growth retardation, delayed puberty.
• Without transfusion, death from heart failure in the first years of life.

Investigations

• Haemoglobin electrophoresis (or HPLC) is the diagnostic test.
• Skull X-ray: "hair-on-end" appearance from marrow expansion; long bones show thin cortices and widened marrow spaces.
• Monitoring for iron overload: serial ferritin, and MRI of the heart and liver where available.

Thalassaemia minor versus iron deficiency

Management of thalassaemia major

The goals are to keep a near-normal haemoglobin, suppress the patient's own ineffective marrow, and prevent iron overload.

Regular transfusion

• Packed red cells, about 15-20 mL/kg every 4-8 weeks (Akbar), keeping haemoglobin above about 10 g/dL (hypertransfusion).
• Benefits: normal growth and activity, bones heal and facial changes are prevented, spleen and liver shrink, less gut iron absorption.
• Use screened blood and give hepatitis B vaccine.

Iron chelation

Each unit of blood adds about 200 mg of iron, and the body has no way to excrete it, so chelation is essential once overload appears and before organ damage.

• Vitamin C in small doses increases iron excretion with deferoxamine.
• Folic acid daily supports the overactive marrow.

Splenectomy

• Indicated for hypersplenism or when transfusion needs exceed about 250 mL/kg/year (Akbar).
• Delay until after 5 years of age.
• Give pneumococcal, Hib and meningococcal vaccines beforehand and penicillin prophylaxis afterwards, because of the risk of overwhelming sepsis.

Curative and newer treatment

• Haematopoietic stem cell transplantation from an HLA-matched sibling is the only established cure; results are best in young children before iron damage.
• Hydroxyurea can raise HbF in some patients (helps mainly intermedia).
• Gene therapy is developing.

Complications

Prevention

• Carrier screening of families, relatives and couples (particularly in consanguineous marriages).
• Genetic counselling for carrier couples.
• Prenatal diagnosis: fetal DNA from chorionic villus sampling (first trimester) or amniocentesis (second trimester).
• Pakistan has provincial thalassaemia prevention programmes and screening laws that may change; check the current national or provincial guideline.

Alpha-thalassaemia in brief

There are four alpha genes (two on each chromosome 16). Losing one causes nothing; two cause alpha-thalassaemia trait (mild microcytosis, normal electrophoresis after infancy); three cause HbH disease (β4 tetramers, moderate haemolytic anaemia); four cause hydrops fetalis with Hb Bart's (γ4), usually fatal in utero.

Prognosis

Without transfusion, thalassaemia major is usually fatal in early childhood. With regular transfusion and good chelation, children grow, go to school and live into adult life; outcome depends mainly on heart and liver iron and endocrine damage. Stem cell transplant offers a cure.

Quick revision

• Autosomal recessive; beta globin gene on chromosome 11.
• Excess alpha chains precipitate: ineffective erythropoiesis and haemolysis.
• Major: well at birth, anaemic by 3-12 months, big liver and spleen, chipmunk face.
• Hair-on-end skull; target cells; HbF high, HbA absent or low.
• Minor: microcytosis, high RBC count, HbA2 raised, ferritin normal; no treatment.
• Transfuse 15-20 mL/kg every 4-8 weeks; keep Hb above about 10 g/dL.
• Chelate when ferritin above about 1000 ng/mL: deferoxamine SC, deferasirox or deferiprone orally.
• Splenectomy after 5 years for hypersplenism; vaccinate and give penicillin.
• Cure: matched sibling stem cell transplant. Prevention: carrier screening and prenatal diagnosis.

Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).

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