Thalassaemia: Genetics, Diagnosis and Transfusion Care

Thalassaemias are inherited disorders in which the body makes too little of one of the globin chains of haemoglobin. Beta thalassaemia is common in Pakistan, where thousands of children are born each year with thalassaemia major and need lifelong blood transfusions. Screening and genetic counselling can prevent many new cases.

Genetics

Thalassaemia is inherited in an autosomal recessive pattern. If both parents carry beta thalassaemia trait, each pregnancy has:

• a 25% chance of thalassaemia major
• a 50% chance of trait
• a 25% chance of an unaffected child

Marriage between relatives (consanguinity), which is common in the region, increases the chance that both parents carry the same gene.

Types of beta thalassaemia

• Beta thalassaemia trait (minor): one gene affected. Usually no symptoms; mild microcytic anaemia.
• Thalassaemia intermedia (non-transfusion-dependent): moderate anaemia; transfusions are needed only sometimes.
• Thalassaemia major (transfusion-dependent): both genes severely affected. Severe anaemia usually appears between 6 and 24 months of age, as fetal haemoglobin falls.

Alpha thalassaemia also exists. Its severity depends on how many of the four alpha genes are deleted.

Clinical features of thalassaemia major

• Severe pallor.
• Poor feeding and failure to thrive.
• Jaundice.
• Enlarged liver and spleen.
• Without adequate transfusion, bone marrow expansion causes:
  • typical facial changes (frontal bossing, maxillary overgrowth)
  • a "hair-on-end" skull X-ray
  • fragile bones

Investigations

• Full blood count: microcytic, hypochromic anaemia. In trait, the red cell count is often high relative to the haemoglobin.
• Blood film:
  • target cells
  • nucleated red cells
  • basophilic stippling
• Haemoglobin analysis (HPLC or electrophoresis):
  • raised HbA₂ (above about 3.5%) in beta thalassaemia trait
  • raised HbF and absent or very low HbA in thalassaemia major
• Ferritin: to exclude iron deficiency.
• DNA analysis: for genetic counselling and prenatal diagnosis.

Management of transfusion-dependent thalassaemia

• Regular red cell transfusions, typically every 2–5 weeks, keeping the pre-transfusion haemoglobin around 95–105 g/L (Thalassaemia International Federation guidance), to allow normal growth and suppress marrow expansion.
• Iron chelation: each transfusion adds iron, which damages the heart, liver and endocrine glands. Chelation with deferasirox, deferoxamine or deferiprone is essential. Monitor with ferritin and, where available, MRI (cardiac T2*).
• Monitoring for complications:
  • heart failure and arrhythmias
  • diabetes
  • hypothyroidism
  • delayed puberty
  • osteoporosis
  • transfusion-transmitted infections (hepatitis B and C, HIV)
• Folic acid supplementation; vaccinations.
• Splenectomy only in selected cases, because of infection risk afterwards.
• Haematopoietic stem cell transplantation from a matched donor can be curative. Gene therapies are emerging in some countries.

Prevention

• Carrier screening, including before marriage, and genetic counselling.
• Prenatal diagnosis (chorionic villus sampling) for at-risk couples.
• Public awareness programmes.

Exam pearls

• Microcytosis with a normal ferritin and high red cell count suggests thalassaemia trait.
• Do not give iron to a child with thalassaemia unless iron deficiency is proven.
• Thalassaemia major presents after 6 months of age, as fetal haemoglobin declines.

See also Iron Deficiency Anaemia, our Paediatrics 2.0 Exam Night notes and the haematology part of the Medicine Companion.

Test yourself

5 exam-style single-best-answer questions. Choose your answer, then tap “Show answer”.

1. Both parents have beta thalassaemia trait. Chance of a child with thalassaemia major in each pregnancy?

   1. 50%
   2. 0%
   3. 100%
   4. 75%
   5. 25%
   Show answer

   Answer: E. 25%
   Autosomal recessive: 25% major, 50% trait, 25% unaffected.

2. Which result supports beta thalassaemia trait?

   1. Hypersegmented neutrophils
   2. Low platelets
   3. Raised HbA2 (above about 3.5%)
   4. Raised MCV
   5. Low ferritin
   Show answer

   Answer: C. Raised HbA2 (above about 3.5%)
   A raised HbA2 on HPLC or electrophoresis is typical of beta thalassaemia trait.

3. At what age does thalassaemia major usually present?

   1. 6–24 months
   2. Adolescence
   3. At birth
   4. Old age
   5. Adulthood
   Show answer

   Answer: A. 6–24 months
   Symptoms appear as fetal haemoglobin declines after about 6 months.

4. Why do transfusion-dependent patients need chelation?

   1. To raise haemoglobin
   2. To prevent clotting
   3. To prevent infection
   4. To treat jaundice
   5. To remove excess iron that damages the heart, liver and endocrine glands
   Show answer

   Answer: E. To remove excess iron that damages the heart, liver and endocrine glands
   Each transfusion adds iron; chelation (deferasirox, deferoxamine, deferiprone) prevents iron overload.

5. Which can be curative for thalassaemia major?

   1. Splenectomy
   2. Folic acid
   3. Vitamin C
   4. Iron supplements
   5. Haematopoietic stem cell transplantation
   Show answer

   Answer: E. Haematopoietic stem cell transplantation
   A matched stem cell transplant can cure the disease; gene therapies are emerging.

More articles in Haematology

• Iron Deficiency Anaemia: Causes, Tests and Iron TreatmentMicrocytic anaemia explained: causes, ferritin and blood film, distinguishing thalassaemia trait, oral and IV iron, and when to investigate the gut.
• Vitamin B12 and Folate Deficiency: Megaloblastic AnaemiaCauses of B12 and folate deficiency, neurological signs, blood film, pernicious anaemia, hydroxocobalamin and why B12 is replaced before folate.

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Disclaimer

For education and exam preparation only. This is not medical advice and must not be used to diagnose or treat patients. Always follow current clinical guidelines and the advice of qualified senior colleagues.