Hereditary spherocytosis: red cell membrane genes, symptoms and treatment

Normal red blood cells are flexible, doughnut-shaped discs. In HS the membrane that surrounds each cell is weaker than it should be, and as the cells squeeze through the spleen, pieces of membrane break off and the cell becomes a sphere. UCLH explains that these spherocytes are easily destroyed and may only last 30 days instead of the normal 120, so the bone marrow cannot always keep up.

The result is haemolysis, the early breakdown of red cells. Sheffield Children's NHS Foundation Trust points out that whether someone becomes anaemic depends on how severe the haemolysis is and how well the bone marrow compensates. People whose haemolysis is fully compensated are not anaemic and usually have a milder course.

UCLH says symptoms differ in severity, can appear at any age and are not always present at birth. Children often resemble affected parents or siblings.

• Anaemia: tiredness, irritability, looking pale or growing less well than expected. Older children and adults may tire on exercise. Those with severe disease may need regular transfusions.

• Jaundice: yellowing of the skin and whites of the eyes as bilirubin builds up. It is reversible and may vary over time. Sheffield Children's warns that HS raises the risk of severe jaundice in the first days after birth, which if not detected and treated can damage the brain, so parents should tell their midwife and doctor about the family history.

• Gallstones: from the breakdown products of red cells. Sheffield Children's says they can cause problems from the late teens onward, and UCLH names repeated abdominal pain, gallbladder inflammation and blockage of the bile duct. The main treatment is removing the gallbladder.

• Enlarged spleen: it can make the abdomen feel full, and UCLH advises avoiding contact sports with a large spleen because it can bleed heavily if damaged.

• Crises: a viral infection such as parvovirus B19 can stop red cell production for up to 10 days or worsen haemolysis, and may need a short period of blood transfusion.

The genes responsible provide instructions for proteins found in the red cell membrane which let the cell change shape without breaking as it passes through narrow capillaries. MedlinePlus Genetics, a US National Library of Medicine resource used here because a UK page lists gene details less fully, says changes in at least five genes cause HS, and that ANK1 accounts for about half of cases. The others are SLC4A1, SPTA1, SPTB and EPB42.

UCLH says DNA analysis of family members can now be used to understand which gene causes the condition and who is affected. Gene results are therefore useful for the whole family but are not needed for the first diagnosis, which relies on clinical assessment and blood tests.

Sheffield Children's says HS is usually inherited as a dominant condition affecting both sexes equally, so sons and daughters of an affected parent each have a 50% risk. About 30% of patients have a recessively inherited form, for which the risk of inheritance is much lower. MedlinePlus Genetics gives about 75% of cases as autosomal dominant.

UCLH reports that three out of four people with HS have a family history and one in four do not. The reasons are that the parents may have a very mild condition that was never diagnosed, or the change is new. A parent who has never had symptoms may therefore still have a mild form, which is one reason relatives are sometimes tested.

Most people with HS have no major problems and need only folic acid, which supports the increased red cell production, according to Sheffield Children's. UCLH says patients are seen in clinic at least once a year. Splenectomy is considered for people severely affected, those with a very large spleen or severe anaemia. Because the red cells work normally apart from their shape, removing the spleen is an effective cure for most people but carries short and long-term risks that need to be weighed, as Sheffield Children's explains. UCLH recommends waiting until a child is 5 years old, and notes that removing only part of the spleen is suggested by some surgeons to preserve some function, though this has not been proven in a clinical trial.

UCLH advises going to A&E for sudden tiredness, poor appetite or feeding, or worsening jaundice or paleness, and seeking urgent advice after an abdominal injury or abdominal pain. People whose spleen has been removed are at higher risk of infection and should get prompt advice for infection, fever or animal bites.