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 crises, acute chest crisis or stroke. The condition is inherited in an autosomal recessive manner and most individuals with sickle cell disease have a specific gene change present in both copies of the gene, beta haemoglobin (HBB).

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 lead to splenic enlargement and severe anaemia.
• 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.

Sickle cell disorder may be diagnosed through the NHS antenatal or neonatal screening programmes, or at clinical presentation.

Antenatal screening:

• All pregnant women in England are offered a blood test for thalassaemia, and those at high risk of being a sickle cell carrier are offered a test for sickle cell.
• Abnormal antenatal haemoglobinopathy screening results may indicate an underlying genetic haemoglobinopathy in the mother, such as thalassaemia or sickle cell disease. These tests also identify mothers that are carriers of a haemoglobinopathy.
• For more information, see:
  • Primary Care presentation: Patient with abnormal antenatal haemoglobinopathy screening
  • Fetal and Women’s Health presentation: Pregnancy where mother is diagnosed with a haemoglobinopathy disease or carrier status confirmed

Newborn screening:

• Sickle cell disease may be diagnosed on newborn blood spot screening, offered routinely to all babies in the UK
• This condition may also be identified through the Generation Study.

Clinical presentation:

• Sickle cell disease may present clinically with features as listed above.
• For information about testing, see Paediatrics presentation: Child with anaemia.

Sickle cell disease is an autosomal recessive condition. If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
• 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
• 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Usually, the parents of affected individuals are carriers for the condition and therefore have a 25% (1-in-4) chance of having another affected child together. Very rarely, de novo variants (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 testing may also be an option under the NHS 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 may be available as a curative therapy for eligible patients for whom a matched related donor is available.

In February 2025, the one-off gene therapy known as exagamglogene autotemcel (or ‘exa-cel’), was approved for use on the NHS in England by the National Institute for Health and Care Excellence as a curative treatment for older children and adults with a severe form of sickle cell disease who would be suitable for a stem cell transplant but where a donor is not available.

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 England: Revolutionary gene-editing therapy for sickle cell ‘offers hope of a cure’ for NHS patients
• NICE: Exagamglogene autotemcel for treating severe sickle cell disease in people 12 years and over
• 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
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Frangoul H, Altshuler D, Cappellini MD and others. ‘CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia.‘ The New England Journal of Medicine 2021: volume 384, issue 3, pages 252–260. DOI:10.1056/NEJMoa2031054
• 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