Sickle cell disease

In sickle cell disease, the red blood cells cannot move normally through small blood vessels due to their unusual shape. This can cause blockage of vessels in various organs, resulting in painful episodes and, more seriously, acute chest crisis or stroke.

Acute presentations

• Dactylitis: Swollen hands and/or feet, most commonly seen in infancy.
• Splenic (or hepatic) sequestration: When a large amount of red blood cells suddenly become trapped in the spleen (or liver), which can cause children to become suddenly very anaemic.
• Painful crises: This can affect any part of the body (bones, for example, or the abdomen).
• Sickle chest crisis: Due to sickling of cells in the lung vessels, severe respiratory compromise can occur – this is a medical emergency.
• Ischaemic stroke: This is caused by sickling of cells in the cerebral vessels.
• Gallstones: This is caused by destruction of blood cells.
• Priapism: A painful erection that won’t go down.

More chronic presentations

• Jaundice.
• Anaemia: Presenting with pallor, weakness and fatigue.
• Some patients will have a large spleen (splenomegaly). Many have a normal-sized spleen, but over time all patients will be functionally asplenic because multiple episodes of ischaemia and/or infarct will impair function to such an extent that individuals will be susceptible to infections.
• Delayed puberty.
• Pulmonary hypertension: High blood pressure in the blood vessels of the lungs.
• Kidney damage: This can lead to bedwetting (secondary to producing large amounts of dilute urine), as well as high blood pressure and kidney stones in older children and adults.
• Liver disease: This is more prominent in older children and adults.
• Poor healing: For example, adult patients can develop leg ulcers that take a very long time to heal.

Carriers of sickle cell disease are generally asymptomatic; however, care should be taken when undergoing anaesthesia to make sure oxygenation is maintained.

Sickle cell disease is caused by pathogenic variants in the beta haemoglobin (HBB) gene. The vast majority of cases occur due to an E6V (glutamate to valine at the sixth amino acid) substitution, causing the misfolding of the protein and haemoglobin polymerisation, which in turn results in the characteristic sickle shape.

For information about testing, see Presentation: Child with anaemia.

Sickle cell disease is an autosomal recessive condition. Usually, the parents of affected individuals are carriers for the condition and therefore have a 25% (one-in-four) chance of having another affected child. Very rarely, de novo mutations (arising for the first time in the sperm or egg cells) can lead to sickle cell disease. Carriers are known as having ‘sickle cell trait’ (HbA/HbS, with HbA being the normal adult haemoglobin and HbS being sickle haemoglobin) and are generally asymptomatic. Those affected by the disease have variants in both copies of the gene (HbS/HbS).

For couples in which one or both individuals have sickle cell trait or the disease, genomic testing can be offered either during pregnancy (via chorionic villus sampling or amniocentesis) or in the neonatal period to determine the genotype of the fetus or baby. Preimplantation genetic diagnosis may also be an option if both individuals in a couple are carriers and have no unaffected children.

Some other combinations of inheritance of HbS from one parent and another haemoglobin disorder from the other parent will also result in a child with a different sickle cell phenotype, such as HbC, HbD or beta thalassemia.

Management of children with sickle cell disease is complex and should be delivered via a multidisciplinary team in a haemoglobinopathy specialist centre. There are national standards of clinical care for children with sickle cell disease (see our resources list below). Supportive care such as penicillin V prophylaxis is vital for affected children; other management includes surveillance for disease complications and therapies such as hydroxycarbamide or blood transfusion. Stem cell transplantation is the only curative therapy currently available, though there are gene therapies undergoing clinical trial in the UK (see the references section below).

For clinicians

• British Society for Haematology: Guidelines
• GeneReviews: Sickle cell disease
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Sickle cell disease
• NHS England: National Genomic Test Directory
• NHS and NICE: Sickle cell acute painful episode: Management of an acute painful sickle cell episode in hospital (PDF, 179 pages)
• OMIM: 603903 Sickle cell disease
• Sickle Cell Society: Paediatric standards
• U.S. National Library of Medicine: ClinicalTrials.gov database

References:

• Hoban MD, Orkin SH and Bauer DE. ‘Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease’. Blood 2016: volume 127, issue 7, pages 839–848. DOI: 10.1182/blood-2015-09-618587

For patients

• NHS Health A to Z: Sickle cell disease
• Patient info: Sickle cell disease and sickle cell anaemia
• Sickle Cell Society