Haemoglobinopathies

Affected individuals may present with chronic haemolytic anaemia, microcytosis, or both, depending on the underlying haemoglobinopathy.

Ineffective erythropoiesis, splenomegaly and, in some forms, iron overload occur in more severe disease.

Vaso-occlusive and hypercoagulable complications are characteristic of sickle cell disease. Clinical severity ranges from asymptomatic carrier states to transfusion-dependent disease and intrauterine foetal hydrops. Age of onset varies across the spectrum:

• Haemoglobin Bart’s hydrops fetalis presents in utero or at delivery.
• major typically becomes evident between 6 and 24 months.
• manifests in infancy, after the foetal-to-adult haemoglobin switch.

Non-transfusion-dependent forms, including haemoglobin H disease, intermedia and haemoglobin E/beta-thalassaemia, are recognised in childhood or later. Carrier states are usually asymptomatic and identified through screening.

Inheritance varies by entity; most genetic haemoglobinopathies follow autosomal recessive inheritance. and thalassaemia require biallelic HBB variants, whereas the clinically significant thalassaemias result from the loss of three of four alpha-globin genes (haemoglobin H disease) or all four (haemoglobin Bart hydrops fetalis). Heterozygous HBB variants can additionally cause autosomal dominant beta-thalassaemia intermedia, in which hyper-unstable beta-globin chains precipitate together with excess unpaired alpha-globin chains and produce markedly ineffective erythropoiesis.

Diagnosis combines full blood count, haemoglobin separation (high-performance liquid chromatography or capillary electrophoresis) and molecular analysis of the globin genes. Targeted analysis of HBB, HBA1 and HBA2, including deletion testing for , identifies the causative variant and defines the genotype.

Main differential diagnoses include:

• Iron deficiency anaemia: microcytosis without abnormal haemoglobin fractions; not globin gene-related.
• Anaemia of chronic disease: microcytic or normocytic anaemia with a systemic cause; not globin gene-related.
• Congenital : microcytic anaemia with ring sideroblasts; ALAS2 and others.
• Hereditary haemolytic anaemias of membrane or enzyme origin: haemolysis without a globin variant; SPTB, ANK1, G6PD, PKLR.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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• GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematol. 2023;10(8):e585-e599. doi: 10.1016/S2352-3026(23)00118-7. PMID: .