75  Other Hemoglobinopathies

75.1 Introduction

Hemoglobinopathies are a diverse group of inherited disorders affecting the structure or production of the globin chains of haemoglobin. While sickle cell disease is the most prevalent and clinically significant hemoglobinopathy in Ghana and West Africa, other disorders—such as thalassemias, unstable haemoglobins, and quantitative or structural variants—also contribute substantially to childhood morbidity. These conditions, though less frequently recognised, are important causes of chronic anaemia, transfusion dependence, and complications such as gallstones, iron overload, and growth failure.

Hemoglobinopathies arise from mutations in the α-globin or β-globin genes, leading to either defective haemoglobin synthesis (thalassemias) or theproduction of abnormal haemoglobin variants. Understanding their pathophysiology is crucial for appropriate diagnosis and management, particularly in resource-limited settings where newborn screening may not yet be widespread, and where chronic haemoglobin disorders may be misdiagnosed as nutritional anaemia or sickle cell disease.

This chapter provides an overview of non-sickle cell hemoglobinopathies relevant to paediatric practice in Ghana, reviews their clinical features and diagnostic approaches, and outlines principles of management.

75.2 Anatomy and Physiology of Haemoglobin

Haemoglobin is a tetrameric protein composed of two pairs of globin chains (α and β in HbA) and four heme groups. Key components include:

  • HbA (α₂β₂): predominant adult haemoglobin
  • HbA₂ (α₂δ₂): minor adult haemoglobin
  • HbF (α₂γ₂): predominant fetal haemoglobin

Globin chain production is genetically regulated:

  • α-globin genes: four genes located on chromosome 16
  • β-globin gene cluster: located on chromosome 11, includes δ, γ, and β genes

Disorders affecting these genes result in imbalances in haemoglobin chain production or thesynthesis of structurally abnormal haemoglobin molecules.

75.3 Classification of Hemoglobinopathies (excluding Sickle Cell Disease)

  1. Thalassemias (quantitative disorders)

    • α-thalassemia
    • β-thalassemia
    • δβ-thalassemia and hereditary persistence of fetal haemoglobin (HPFH)

  2. Structural variants (qualitative disorders)

    • Haemoglobin C (HbC)
    • Haemoglobin E (HbE)
    • Haemoglobin D and others

  3. Unstable hemoglobins

  4. Methemoglobinemia and related hemoglobin variants

While many are asymptomatic carriers, homozygous or compound heterozygous states may cause significant disease.

75.4 α-Thalassemia

75.4.1 Pathophysiology

α-Thalassemia results from the deletion or mutation of one or more of the four α-globin genes. The clinical severity corresponds to the number of genes affected:

  • One-gene deletion (α⁺ trait): silent carrier
  • Two-gene deletion (α-thalassemia trait): mild microcytic anaemia
  • Three-gene deletion (HbH disease): moderate to severe chronic hemolytic anaemia
  • Four-gene deletion (Hb Bart’s hydrops fetalis): incompatible with life

In West Africa, single-gene deletions are more common, contributing to high rates of microcytosis often misinterpreted as iron deficiency anaemia.

75.4.2 Clinical Features

  • Silent carriers: asymptomatic
  • α-thalassemia trait: mild anaemia, microcytosis, borderline Hb
  • HbH disease:
    • Chronic hemolysis
    • Jaundice
    • Splenomegaly
    • Episodes of hemolytic crises, especially with infections or oxidative stress
    • Growth faltering

75.4.3 Diagnosis

  • CBC: microcytosis, hypochromia, elevated RBC count
  • Peripheral smear: target cells, inclusion bodies (HbH)
  • Hb electrophoresis: usually normal except in HbH disease (presence of HbH or Hb Bart’s)
  • DNA testing: confirms deletions (limited availability in Ghana)

75.4.4 Management

  • Folic acid supplementation
  • Avoid oxidative drugs (e.g., sulphonamides)
  • Transfusions during acute crises
  • Splenectomy may be considered in severe HbH disease (with appropriate vaccination)
  • Genetic counselling is necessary for families

75.5 β-Thalassemia

75.5.1 Pathophysiology

β-Thalassemia results from point mutations affecting β-globin gene expression. It is less common in West Africa but occurs sporadically due to population migration. β-Thalassemia leads to reduced (β⁺) or absent (β⁰) β-chain production, causing α-chain excess, ineffective erythropoiesis, and hemolysis.

75.5.2 Types

  • β-thalassemia minor (trait): heterozygous carriers
  • β-thalassemia intermedia: moderate disease
  • β-thalassemia major (Cooley’s anaemia): severe, transfusion-dependent from infancy

75.5.3 Clinical Features

75.5.3.1 β-Thalassemia Minor

  • Mild anemia
  • Microcytosis
  • Asymptomatic

75.5.3.2 β-Thalassemia Major

  • Severe anaemia appearing at 3–6 months
  • Failure to thrive
  • Jaundice
  • Hepatosplenomegaly
  • Bone changes (frontal bossing, maxillary prominence)
  • Recurrent infections
  • Gallstones
  • Cardiac failure and endocrine dysfunction due to iron overload

75.5.4 Diagnosis

  • CBC: severe microcytic hypochromic anaemia
  • Electrophoresis: low HbA, elevated HbF and HbA₂
  • Serum ferritin: elevated with transfusions
  • Radiology: bone changes in poorly transfused children

75.5.5 Management

  • Regular transfusion regimen to maintain Hb > 9–10 g/dL
  • Iron chelation therapy (deferoxamine, deferiprone, deferasirox)
  • Endocrine screening (thyroid, diabetes, puberty disorders)
  • Splenectomy for hypersplenism
  • Curative therapy: bone marrow transplantation — limited availability in West Africa
  • Genetic counselling

In Ghana, limited access to electrophoresis and transfusion challenges often delay diagnosis.

75.6 Hemoglobin C (HbC) Disease

75.6.1 Epidemiology

HbC is common in West Africa, including Ghana. The HbC gene frequency is highest in northern Ghana and Burkina Faso.

75.6.2 Pathophysiology

A substitution of lysine for glutamic acid at position six on the β-globin chain. HbC tends to crystallise within red cells, leading to reduced RBC lifespan.

75.6.3 Clinical Forms

  • HbAC (trait): asymptomatic
  • HbCC (homozygous):
    • Mild to moderate haemolytic anaemia
    • Splenomegaly
    • Intermittent jaundice
    • Pigment gallstones

75.6.4 Diagnosis

  • Electrophoresis: predominant HbC
  • Blood film: target cells, crystals

75.6.5 Management

  • Generally benign condition
  • Supportive care
  • Monitor for gallstones
  • Folic acid supplementation

75.7 Haemoglobin E (HbE)

75.7.1 Epidemiology

Common in Southeast Asia; rare in Ghana but seen in children of immigrant families or mixed ancestry.

75.7.2 Clinical Features

  • HbE trait: asymptomatic
  • HbE disease: mild anaemia
  • HbE/β-thalassemia: significant anaemia, similar to β-thalassemia intermedia

75.7.3 Diagnosis and Management

  • Electrophoresis shows the HbE band.
  • Management mirrors β-thalassemia intermedia (occasional transfusion, iron monitoring)

75.8 δβ-Thalassemia and HPFH

75.8.1 δβ-Thalassemia

  • Reduced δ and β chain production
  • Elevated HbF
  • Moderate anemia

75.8.2 Hereditary Persistence of Fetal Haemoglobin (HPFH)

  • Benign persistence of HbF into adulthood
  • Often asymptomatic
  • Important in genetic counselling due to interaction with other variants

75.9 Unstable Hemoglobins

These are rare variants with reduced molecular stability leading to chronic hemolysis.

75.9.1 Features

  • Chronic hemolytic anaemia
  • Heinz bodies on staining
  • Episodes precipitated by illness or oxidant drugs

75.10 Methemoglobinemia

Specific haemoglobin variants predispose to methaemoglobinemia, presenting with cyanosis unresponsive to oxygen therapy.

75.10.1 Clinical Features

  • “Chocolate-brown” blood
  • Cyanosis
  • Normal PaO₂ despite low saturation

75.10.2 Management

  • Methylene blue for acquired forms
  • Congenital forms may require long-term monitoring.

75.11 Clinical Presentation of Hemoglobinopathies

Children may present with:

  • Chronic anemia
  • Jaundice
  • Poor growth
  • Splenomegaly
  • Bone pain (in thalassemia)
  • Recurrent infections
  • Gallstones
  • Transfusion dependence

In Ghana, such features are often mistakenly attributed to sickle cell disease, malaria, or iron deficiency, highlighting the need for improved diagnostics.

75.12 Differential Diagnosis

  • Iron deficiency anaemia
  • Sickle cell syndromes
  • Chronic infection (e.g., TB, HIV)
  • Hemolytic anemias (G6PD deficiency)

75.13 Investigations

  • CBC and blood film
  • Reticulocyte count
  • Hb electrophoresis or HPLC
  • Serum ferritin
  • Liver function tests
  • Ultrasound (hepatosplenomegaly, gallstones)

75.14 Management Principles

  1. Accurate diagnosis
  2. Regular follow-up
  3. Transfusion support for moderate/severe disease
  4. Iron overload monitoring and chelation
  5. Nutritional support (folate, vitamin D assessment)
  6. Splenectomy in selected cases
  7. Vaccinations
    • Pneumococcal
    • Meningococcal
    • Hib
  8. Family and genetic counselling

75.15 Complications

  • Gallstones
  • Iron overload (endocrine, cardiac, hepatic complications)
  • Growth failure
  • Splenomegaly
  • Osteopenia
  • Cardiac failure (especially in β-thalassemia major)

75.16 Local Context: Ghana and West Africa

  • Haemoglobin C trait is common in northern Ghana.
  • α-thalassemia trait contributes significantly to microcytosis in Ghanaian children and is often confused with iron deficiency.
  • Limited access to electrophoresis, DNA analysis, and HPLC leads to underdiagnosis.
  • Blood transfusion availability can be inconsistent, complicating management for thalassemia major.
  • Iron chelation therapy is expensive and often unavailable.
  • Newborn screening programs in Ghana currently focus mainly on sickle cell disease, leaving other hemoglobinopathies undetected.

75.17 Key Points for Clinical Practice

  • Always evaluate microcytosis that does not respond to iron therapy for thalassemias.
  • Consider hemoglobinopathy in any child with chronic hemolytic anaemia without sickling crises.
  • HbC disease may cause gallstones at a young age—consider abdominal ultrasound in symptomatic children.
  • Ensure early transfusion and chelation for suspected thalassemia major.
  • Provide comprehensive counselling to families, including future reproductive implications.

75.18 Further Reading

  1. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. Oxford University Press.
  2. Hoffbrand AV, Higgs DR, Keeling D, Mehta AB. Postgraduate Haematology. Wiley-Blackwell.
  3. Ohene-Frempong K. Hemoglobinopathies in Africa. Pediatric Clinics of North America.
  4. Ministry of Health Ghana & Ghana Health Service. National Newborn Screening Guidelines.
  5. Modell B, Darlison M. Global epidemiology of hemoglobin disorders. Bulletin of the WHO.