Hereditary spherocytosis: what is it, causes, symptoms, treatment, prognosis

What is hereditary spherocytosis?

Hereditary spherocytosis (abbr. NS, syndrome/Minkowski-Shoffard anemia) Is a hereditary disease that affects erythrocytes. The characteristic symptoms of hereditary spherocytosis are the destruction of red blood cells in the spleen and their removal from the bloodstream (hemolytic anemia), yellowing of the skin (jaundice) and enlargement of the spleen (splenomegaly).

Minkowski-Shoffard anemia affects about 1 in 2,000 people. NS results from genetic changes in five different genes; ANK1, SLC4A1, SPTA1, SPTB and EPB42. The age of onset varies, but often occurs between the ages of 3 and 7. Symptoms may develop in infancy, but some people with hereditary spherocytosis have no or minor symptoms and are diagnosed later in life.

The suspicion of Minkowski-Shoffard anemia is based on clinical features and a family history of spherocytosis or related symptoms. The diagnosis is confirmed by a blood test. Surgical removal of the spleen (splenectomy) is used as a treatment for Minkowski-Shoffard anemia in severe anemia. Other treatments include folate (vitamin B9) and blood transfusions.

Signs and symptoms

Hereditary spherocytosis is divided into mild, moderate and severe forms of the disease. The classification is based on the amount of hemoglobin, reticulocytes and bilirubin and the amount of spectrin in erythrocytes. Hemoglobin transports oxygen in the blood. Reticulocytes are immature erythrocytes. Bilirubin is formed in the liver when hemoglobin breaks down. Spectrin is a protein that helps keep cells in shape. A decrease in hemoglobin and spectrin and an increase in reticulocytes and bilirubin are associated with more severe NS. People with severe disease are usually diagnosed at a younger age than people with moderate to mild Minkowski-Shoffard anemia. Those with mild HC may have compensated hemolysis. This means that red blood cells are created at the same rate as they are destroyed. These people have no noticeable symptoms and are therefore diagnosed at a later age.

In people with hereditary spherocytosis, the red blood cells are round, ball-like (spherocytes) rather than the typical donut shape. These cells are more likely to be destroyed by stress than normal red blood cells (osmotic fragility). Most often, patients with NS have the following symptoms:

• anemia;
• enlargement of the spleen (splenomegaly);
• yellowing of the skin or eyes (jaundice).

Anemia can cause extreme tiredness and pale skin. Splenomegaly can cause abdominal pain. People with HC often seek treatment for recent or ongoing fever or infection. Other signs are less common in people with Minkowski-Shoffard syndrome. These include an enlarged liver (hepatomegaly), growth disorders and allergic diseases. Some people with HC who are diagnosed with the disease during infancy may need regular blood transfusions (transfusion dependence). However, as a rule, the need for blood transfusion decreases with age.

The most common problem seen in people with hereditary spherocytosis is the development of gallstones (cholelithiasis). Gallstones can be detected using ultrasound, allowing early diagnosis and treatment. People with HC may also have hemolytic, aplastic, and megaloblastic crises. Hemolytic crises are often caused by viral diseases and cause more destruction of red blood cells. Blood transfusion may be required, but the hemolytic crisis is usually mild. Aplastic crises are less common and more severe than hemolytic crises, but are also caused by viral diseases, especially the B19 parovirus. After a person has been infected with the B19 parovirus, they remain immune for the rest of their lives. Megaloblastic crises are caused by a lack of vitamin B9 (folate). Children, pregnant women, and people recovering from aplastic crises need more folate, so they are more susceptible. Folate supplementation can also prevent megaloblastic crises.

In people with HC, the tissue that makes blood cells can grow outside the bone marrow, where it usually resides (extramedullary hematopoiesis). There have also been reports of leg ulcers, blood cancer and small cracks in the retinal layer at the back of the eye (angioid stripes). However, these problems are not considered common and have been reported in only a few people with Minkowski-Shoffard syndrome / anemia.

Causes

Hereditary spherocytosis is caused by changes (mutations) in five different genes that code for proteins that are part of the erythrocyte membrane. These genes are ANK1, SLC4A1, SPTA1, SPTB and EPB42. NS is inherited in an autosomal dominant manner in 75% of cases, and in an autosomal recessive manner in 25% of cases.

We all have two copies of all our genes. One copy is passed on from mom and another from dad.

Recessive genetic disorders occur when a person inherits an abnormal gene from each parent. If a person receives one normal gene and one abnormal gene for a disease, the person will be a carrier of the disease, but usually asymptomatic. The risk that two carrier parents will both pass on the abnormal gene and therefore infect the baby is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with each pregnancy. The probability for a child to receive normal genes from both parents is 25%. All probabilities are the same for men and women.

Dominant genetic disorders occur when only one copy of an abnormal gene is needed to cause a specific disorder. The abnormal gene can be inherited from either parent or be the result of a gene mutation (change) in the affected person. The risk of passing the abnormal gene from the affected parent to the offspring is 50% with every pregnancy. The risk is the same for men and women.

Disease-causing changes in genes associated with HC cause defects in erythrocyte membrane proteins. This reduces the surface area of ​​the cells and leaves the cells unable to reshape under pressure. These are rounded spherocytes. Spherocytes enter the spleen. In the spleen, spherocytes are further damaged and many are destroyed. Those that have escaped the spleen return to the circulation.

Affected populations

Hereditary spherocytosis affects approximately 1 in 2,000 people. Genetic changes that are more common in certain groups of people (founder mutations) have not been reported. NS affects men and women equally. The age at diagnosis of NA is often in the range of 3-7 years, but it can manifest itself immediately in infancy with a severe course or in adulthood with a mild course.

Diagnostics

Hereditary spherocytosis is suspected for the first time on the basis of the clinical presentation. People with Minkowski-Shoffard anemia often have one or more characteristic features; anemia, splenomegaly, or jaundice. Jaundice is the most common condition that develops in young children. Other common reasons people with HC see a specialist are anemia of unknown cause or anemia that is resistant to iron supplements. Family history data suggest whether there are relatives with a diagnosis of hereditary spherocytosis, any characteristic signs or history of surgical removal of the spleen (splenectomy) or gallbladder (cholecystectomy).

To search for spherocytes, a general blood test is performed to determine the number of immature red blood cells (reticulocytes) and the shape of the red blood cells. It is also important to exclude autoimmune hemolytic anemia. This can be done with a direct antiglobulin test. This test can determine if the destruction of red blood cells is caused by an abnormal immune response.

If the diagnosis is unclear after the clinical examination and laboratory tests described above, additional laboratory tests may be required. The eosin-5 maleimide (e5m) binding test is the most accurate assay. The e5m binding test looks for membrane proteins involved in disease in a sample of red blood cells. If these proteins are absent, the result suggests NA.

If it is necessary to confirm the diagnosis of HC, erythrocyte membranes can be analyzed using gel electrophoresis. This test can tell how much red blood cells are damaged, but this test may not show damage in very mild cases.

Standard treatments

Folic acid supplementation is recommended for people with moderate to severe HC and for all pregnant women with HC. Supplementation probably won't be needed for people with mild hereditary spherocytosis. Some patients need a blood transfusion. Patients should receive blood that matches their blood type, from which white blood cells (leukocytes) have been removed.

Basically, surgical removal of the spleen (splenectomy) can heal NS. However, there is an increased risk of severe infection after surgery. Therefore, recommendations for splenectomy differ depending on the severity. Splenectomy is recommended for patients with severe NS. For patients with moderate illness, the decision to undergo splenectomy should be based on spleen size and quality of life. Splenectomy is not recommended in patients with mild hereditary spherocytosis. If possible, splenectomy should be delayed until 6 years of age or older. For these patients, a minimally invasive (laparoscopic) splenectomy is recommended, subject to the availability of a qualified surgeon and appropriate equipment. After splenectomy, people are often vaccinated and given antibiotic prophylaxis to reduce the risk of infection.

Forecast

Patients with very mild NS can remain unaffected by their disorder if it is not caused by an environmental stressor. In patients undergoing splenectomy, the survival of red blood cells is dramatically improved, and most of them are able to maintain normal hemoglobin levels.

Dutch study of 132 children and adolescents with hereditary spherocytosis, of whom 48 suffered splenectomy, concluded that overall these patients have a strong ability to cope with disease.

Patients with NS who have not undergone splenectomy are thought to have an increased risk of blunt injury to the spleen from trauma due to splenomegaly.