Normal newborn has 90%+ HbF (alpha-gamma chains), dropping with age. In childhood, normal HbF is <2%. HbA2 (alpha-delta instead of alpha-beta) is normally <3.5%, and HbA:HbA2 ratio should be at least 40:1.

Alpha thalassaemia

4 genes for alpha chains. Africans, Afro-Caribbean (provided no Chinese ancestry), South Asians tend to carry the deletional α+ allele (“alpha plus” thalassaemia) which has no health consequences for person or their children (but causes endless confusion…). If both parents have alpha plus, child can just end up alpha plus.

Mediterranean, Middle Eastern, East Asian, SE Asian can have alpha plus or “–” (“zero”) defect, that is more serious.

• If alpha zero, there is usually mild microcytic anaemia, easily confused with iron deficiency. No treatment required, though. Risk of “HbH” disease if other parent alpha plus – abnormal tetramers form viz Hb Barts (4 deltas) and HbH (4 betas). There is mild to moderate anaemia, Heinz bodies (accumulations of excess beta chains) and splenomegaly. Most people do not need any treatment, however.
• If both parents alpha zero, risk of all 4 alpha genes being abnormal – “alpha zero major” – survival is not possible. The baby develops hydrops (as the unstable Hb forms do not deliver oxygen appropriately, so organ failure), and death occurs in utero or soon after birth.

Electrophoresis will show high quantities of Hb Barts in alpha zero thal major. In the trait form, there are often normal levels of HbA and HbA2 so need to do gene deletions.

Beta thalassaemia

Seen in the Mediterranean, Africa, SE Asia. Just 2 genes, so a heterozygote is a carrier, may have mild microcytic anaemia. In the Mediterranean form, the gene is usually a zero producer, so the disease is more severe than in Africa, where production is reduced but not absent.

Beta thal Major (homozygous) present after 6 months of age with anaemia, frontal bossing, growth failure, hepatosplenomegaly.

In Beta-thal trait, HbA2 is obviously increased eg 3.5-7%, and ratio reduced eg 20:1. The only exception is if there is co-existing severe iron deficiency. In beta-thal disease, you may not see such an increase if there’s lots of HbF around (about half the cases), and increased HbF is not specific; but the clinical picture doesn’t leave much doubt. Inclusions (alpha chains) seen esp post splenectomy. Retic count surprisingly normal due to severe intramedullary erythroblast destruction.

Treatment is with folate and regular blood transfusion, which then leads to cirrhosis, pigmentation, diabetes etc. Splenectomy reduces transfusion requirements but because of the increased vulnerability to pneumococcal infection this is usually deferred until later childhood.

Deferipone is oral chelating agent, used in Europe but not licensed in US. Acrimonious debate between lead researcher and drug company about research.

An intermediate beta thal exists, where transfusion is only required at times of increased stress.

Combined alpha thalassaemia and sickle cell disease tends to give less anaemia, but more vaso-occlusive crises.

Family support at https://ukts.org/