Globin gene switching during development

Globin gene switching during development

Sickle cell anaemia (homozygous SS, |3S|3S), HbSC (|3S|3C), HbS/|3+ or |3° thalassaemia, and HbSD (|3S|3D) all produce significant symptoms but homozygous sickle cell anaemia is generally the most severe. The gene has remained at high frequency due to conferred resistance to malaria in het-72 erozygotes. Inheritance is autosomal recessive.

Sickle cell anaemia (SCA, HbSS) Pathogenesis

Widespread throughout Africa, Middle East, parts of India and Mediterranean. Single base change in |3 globin gene, amino acid 6 (glu—>val). In UK Afro-Caribbean population gene is found in —1:10. RBCs containing HbS deform (elongate) under conditions of reduced oxygenation, and form characteristic sickle cells—do not flow well through small vessels, and are more adherent than normal to vascular endothe-lium, leading to vascular occlusion and sickle cell crises. Patients with SCA are the offspring of parents both of whom are carriers of the |3S gene, i.e. they both have sickle cell trait, and homozygotes for the abnormal |3S gene demonstrate features of chronic red cell haemolysis and tissue infarction.

Clinical features

Highly variable. Many have few symptoms whilst others have severe and frequent crises, marked haemolytic anaemia and chronic organ damage. HbF level plays role in ameliorating symptoms (4 HbF—»fewer and milder crises). History may reveal a +ve family history or past history of crises.

• Infancy—newborns have higher HbF level than normal adult, protected during first 8-20 weeks of life. Symptoms start when HbF level falls. SCA often diagnosed <1 year.

• Infection —high morbidity and mortality due to bacterial and viral infection. Pneumococcal septicaemia (Streptococcus pneumoniae) well recognised. Other infecting organisms: meningococcus (Neisseria meningitidis), Escherichia coli and Haemophilusinfluenzae (hyposplenic).

• Anaemia —children and adults often severely anaemic (Hb —6.0-9.0 g/dL). Anaemia is chronic and patients generally well-adapted until episode of decompensation (e.g. severe infection) occurs.

Sickle crises

• Vaso-occlusive —dactylitis, chest syndrome and girdle syndrome. Patients complain of severe bone, joint and abdominal pain. Bone pain affects long bones and spine, and is due to occlusion of small vessels. Triggers: infection, dehydration, alcohol, menstruation, cold and temperature changes-often no cause found.

• Dactylitis —mainly children. Metacarpals, metatarsals, backs of hands and feet swollen and tender (small vessel occlusion and infarction). Recurrent, can result in permanent radiological abnormalities in bones of the hands and feet (rare).

• Acute chest syndrome —common cause of death. Chest wall pain, sometimes with pleurisy, fever and SOB. Resembles infection, infarction or embolism. Requires prompt and vigorous treatment. Transfer to ITU if pO2 cannot be kept >70 mmHg on air. 10% mortality. Treat infection vigorously, often due to S pneumoniae, H influenzae, Mycoplasma, Legionella.

• Aplastic crises —sudden 5 in marrow production (esp. red cells). Parvovirus B19 infection is cause (invades developing RBCs). Mostly self-limiting and after 1-2 weeks the marrow begins to function nor- 73 mally. Top-up transfusion may be needed.

• Haemolytic crises —uncommon; markedly reduced red cell lifespan. May be drug-induced, 2° to infection (e.g. malaria) or associated G6PD deficiency.

• Sequestration crises —mainly children (30%). Pooling of large volumes of blood in spleen and/or liver. Severe hypotension and profound anaemia may result in death.

• Other problems

- Growth retardation: common in children, but adult may have normal height (weight tends to be lower than normal). Sexual maturation delayed.

- Locomotor:Avascular necrosis of the head of the femur or humerus, arthritis and osteomyelitis (Salmonella infection). Chronic leg ulceration is complication of many haemoglobinopathies including sickle cell anaemia. Ischaemia is main cause.

- Genitourinary:Renal papillary necrosis—►haematuria and renal tubular defects. Inability to concentrate urine. Priapism in ~60% males. Less common if HbFt. Frequent UTIs in women, CRF in adults.

- Spleen: Severe pain (infarction of splenic vessels). Spleen may enlarge in early life but after repeated infarcts diminishes in size (—►hyposplenism by 9-12 months of age). Splenic function is impaired.

- Gastrointestinal: Gallstones common (2° to chronic haemolysis). Derangement of LFTs (multifactorial).

- CVS:Murmurs (anaemia), tachycardia.

- Eye:Proliferative retinopathy (in 30%), blindness (esp. HbSC), retinal artery occlusion, retinal detachment.

- CNS:Convulsions, TIAs or strokes, sensory hearing loss (usually temporary).

- Psychosocial:Depression, socially withdrawn. Laboratory features

Anaemia usual (Hb ~6.0-9.0 g/dL in HbSS although may be much lower; HbSC have higher Hb). Reticulocytes may be 4 (to ~10-20%) reflecting intense bone marrow production of RBCs. Anaemic symptoms usually mild since HbS has reduced O2 affinity. MCV and MCH are normal, unless also thalassaemia trait (25% cases). Blood film shows marked variation in red cell size with prominent sickle cells and target cells; basophilic stippling, Howell-Jolly bodies and P appenheimer bodies (hyposplenic features after infancy). Sickle cell test (e.g. sodium dithionate) will be positive. Does not discriminate between sickle cell trait and homozygous disease. Serum bilirubin often 4 (due to excess red cell breakdown).

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