Alpha thalassaemia

Alpha-thalassaemia results from reduced or absent output of alpha globin chains, encoded by the HBA1 and HBA2 genes. A normal individual carries four alpha globin alleles, and the clinical picture depends on how many remain functional. Loss of a single allele produces the silent carrier state (alpha-thalassaemia minima), which is clinically asymptomatic. Loss of two alleles produces the alpha-thalassaemia trait (alpha-thalassaemia minor), with mild microcytic, hypochromic red cell indices but usually no clinically relevant anaemia. The two clinically significant forms arise from loss of three or four alleles.

Hb Bart’s hydrops fetalis syndrome is the severe form, caused by deletion or inactivation of all four alpha globin alleles (–/–). It presents prenatally with generalised oedema, pleural and pericardial effusions, and congestive heart failure secondary to severe anaemia. Extramedullary erythropoiesis, hepatosplenomegaly and a markedly enlarged placenta are typical. Without intervention, death usually occurs in the perinatal or neonatal period.

HbH disease, most often caused by deletion or inactivation of three alpha globin alleles (–/-α), shows a broad phenotypic spectrum. It usually presents in the first years of life but may be recognised in adulthood or as an incidental finding. Features include splenomegaly, sometimes hepatomegaly, mild jaundice and chronic haemolysis, with acute haemolytic episodes triggered by infection or oxidant drugs. Gallstones and thalassaemia-like bone changes may occur. Non-deletional HbH disease tends to be more severe and may become transfusion-dependent.

Clinically significant alpha-thalassaemia is rare in Central Europe, where carrier states are the more common diagnostic consideration in unexplained microcytosis. The clinically significant forms are more frequent in populations originating from Southeast Asia, the Mediterranean, the Middle East and Africa.

Alpha-thalassaemia results from germline pathogenic variants in HBA1 and HBA2, the two alpha-globin genes on chromosome 16p13.3. Each individual normally carries four alpha globin alleles, two on each chromosome 16; their deletion or inactivation reduces alpha globin synthesis and produces an imbalance between alpha and beta globin chains. Overall severity is driven mainly by the number of deleted or inactivated alpha globin alleles and by whether the lesion is deletional or non-deletional. For non-deletional point variants, HBA2 contributes more alpha globin than HBA1, so an equivalent HBA2 variant tends to cause the more severe phenotype. Common lesions include large deletions affecting one or both alpha genes on a chromosome, alongside non-deletional point variants such as Hb Constant Spring in HBA2.

Alpha-thalassaemia is inherited in an autosomal recessive manner; the clinically significant forms arise when alpha-globin function is lost on both chromosomes 16. For Hb Bart’s hydrops fetalis syndrome, where both parents carry a two-gene cis deletion (–/αα), each pregnancy carries a 25% risk of an affected (–/–) foetus, a 50% risk of alpha-thalassaemia trait and a 25% chance of a non-carrier. For HbH disease, the recurrence risk depends on the specific parental genotypes. Carrier testing is informative in at-risk populations, and couples both carrying a two-gene cis deletion can be identified before pregnancy as at risk for an Hb Bart foetus. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.