August 05, 2019
Years published: 1986, 1987, 1988, 1989, 1990, 1993, 2002, 2007, 2019
NORD gratefully acknowledges Ellie Westfall, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Hereditary spherocytosis (HS) is an inherited disease that affects the red blood cells. Characteristic symptoms of HS are the destruction of red blood cells in the spleen and their removal from the blood stream (hemolytic anemia), a yellow tone to the skin (jaundice), and an enlarged spleen (splenomegaly). HS affects about 1 in 2,000 individuals in North America. People with HS have been reported in other areas of the world as well. HS is caused by genetic changes in five different genes; ANK1, SLC4A1, SPTA1, SPTB, and EPB42. Age of onset varies, but often occurs between 3 – 7 years of age. Symptoms can develop in infancy, but some people with HS have no symptoms or minor symptoms and are diagnosed later in life. Suspicion for HS is based on clinical features and a family history of spherocytosis or related symptoms. Diagnosis is confirmed based on blood tests. Surgical removal of the spleen (splenectomy) is used as a cure for HS in the case of severe anemia. Other treatments include extra folate (folate supplementation) and blood transfusions.
HS is divided into mild, moderate, and severe forms of the disease. Classification is based on the amounts of hemoglobin, reticulocytes, and bilirubin and the amount of spectrin in red blood cells. Hemoglobin transports oxygen in the blood. Reticulocytes are immature red blood cells. Bilirubin is formed in the liver when hemoglobin is broken down. Spectrin is a protein that helps keep the shape of a cell. Decreased hemoglobin and spectrin and increased reticulocytes and bilirubin are associated with more severe HS. People with severe HS are usually diagnosed at younger ages than those with moderate or mild disease. Those with mild HS may have compensated hemolysis. This means that red blood cells are created at the same rate as they are destroyed. These individuals may not have noticeable symptoms, and thus be diagnosed later in life.
People with HS have red blood cells that are round like a ball (spherocytes) instead of the typical donut shape. These cells are more likely to break down under stress than normal red blood cells (osmotic fragility). The most common findings in people with HS are anemia, an enlarged spleen (splenomegaly), and a yellow tone to the skin or eyes (jaundice and icterus, respectively). Anemia can cause extreme tiredness (fatigue) and a pale tone of the skin (pallor). Splenomegaly can cause stomach pain. People with HS often present to care with recent or ongoing fever or infection. Other findings in people with HS are less common. These include an enlarged liver (hepatomegaly), growth failure, and allergic diseases. Some people with HS who are diagnosed in infancy may require regular blood transfusions (transfusion dependency). However, typically they grow out of transfusion dependency as they get older.
The most common problem seen in people with HS is gallstone development (cholelithiasis). Gallstones can be detected by ultrasound, which allows early diagnosis and treatment. People with HS may also have hemolytic, aplastic, and megaloblastic crises. Hemolytic crises are often triggered by viral illness and cause more destruction of red blood cells. Blood transfusions may be needed, but hemolytic crises are typically mild. Aplastic crises are less common and more severe than hemolytic crises, but are also triggered by viral illness, particularly parovirus B19. After an individual has been infected with parovirus B19, they are immune for the rest of their lives. Megaloblastic crises are caused by not having enough folate. Children, pregnant women, and people recovering from aplastic crises need more folate, so they are more susceptible. Folate supplementation can prevent megaloblastic crises.
In people with HS, the tissue that creates blood cells may grow outside of the bone marrow, where it is typically found (extramedullary hematopoiesis). There have also been reports of leg ulcers, cancers of the blood, and small cracks in a layer of the retina at the back of the eye (angioid streaks). However, these problems are not believed to be common and have only been reported in a few people with HS.
HS is caused by changes (mutations) in five different genes that code for proteins that are part of the membrane of red blood cells. These genes are ANK1, SLC4A1, SPTA1, SPTB, and EPB42. HS is inherited in an autosomal dominant manner 75% of the time and an autosomal recessive manner 25% of the time.
We all have two copies of all our genes. One copy is passed down from mom and one is passed down from dad.
Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Disease-causing changes in the genes associated with HS cause defects in membrane proteins of red blood cells. This reduces the surface area of the cells and leaves the cells unable to change shape under pressure. These are the rounded spherocytes. Spherocytes are trapped in the spleen. In the spleen, spherocytes are further damaged and many are destroyed. Those that escape the spleen re-enter circulation.
HS affects 1 in 2,000 people in North America. It also occurs in other regions of the world, although not as well studied. No genetic changes that are more common in certain groups of people (founder mutations) have been reported. HS affects males and females equally. Age at diagnosis of HS is often between 3 – 7 years but can occur in infancy with severe disease or into adulthood with mild disease.
HS is first suspected based on the clinical picture. People with HS often present with one or more of the characteristic features; anemia, splenomegaly, or jaundice. Jaundice is the most common feature that develops in young infants. Other common reasons that people with HS see a specialist are anemia with an unknown cause or anemia that is resistant to iron supplementation. The family history is suggestive if there are relatives with a diagnosis of HS, any of the characteristic features, or a history of surgical removal of the spleen (splenectomy) or gallbladder (cholecystectomy).
A blood draw will be done to get a complete blood count, an immature red blood cell (reticulocyte) count, and a look at the shape of red blood cells to look for spherocytes. It is also important to rule out autoimmune hemolytic anemia. This can be done with a direct antiglobulin test. This test can tell whether destruction of red blood cells is caused by an improper immune reaction.
If the diagnosis is unclear after clinical examination and the laboratory tests described above, more laboratory tests may be needed. The eosin-5’-maleimide (EMA) binding test is the most accurate screen for HS. The EMA binding test looks for the membrane proteins involved in HS in a red blood cell sample. If these proteins are missing, the result suggests HS.
If the diagnosis of HS needs to be confirmed, analysis of red blood cell membranes can be done by gel electrophoresis. This test can tell how much the red blood cells are damaged but may not identify very mild cases.
Clinical Testing and Work-Up
The initial evaluation for HS involves a physical examination, a discussion of family history, and the laboratory tests described above on blood samples. Genetic testing is not needed to diagnose HS but can provide more information about the diagnosis and the chance that offspring will have HS. After a specific gene mutation is found in the person who is affected, at-risk family members can be tested for it.
After diagnosis, children should follow up with a physician who specializes in diseases related to blood (hematologist) annually. These visits are used to monitor overall health, growth, spleen size, exercise tolerance, and possibly folate levels. A complete blood count is not needed unless symptoms develop. Ultrasound can be done to screen for gallstones starting at age 5 and should be repeated every 3 – 5 years unless symptoms develop. Children who are severely affected should have a complete blood count done during viral illnesses. Blood transfusions should have had white blood cells removed (leucodepletion) and should be matched to the recipient’s blood type.
Adults with mild HS may not need annual visits with a hematologist. However, yearly follow-up may be helpful for those with moderate or severe disease. Adults with moderate or severe HS can receive ultrasound monitoring for gallstones. Those who have had their spleen surgically removed (splenectomy) may also require more vaccinations or preventative antibiotics. Those who have not had a splenectomy may need their fasting iron status (transferrin saturation) checked annually.
Over the counter folate supplementation is recommended for people with moderate or severe HS and all pregnant women with HS. Supplementation is probably not needed for those with mild HS. Blood transfusions are only necessary in a few people with HS and most grow out of needing them. However, those people should receive blood that is matched to their blood type and has had the white blood cells removed.
Surgical removal of the spleen (splenectomy) essentially cures HS. However, after surgery, there is an increased risk of severe infection. Therefore, the recommendation for splenectomy differs based on severity. People with severe HS are recommended to have a splenectomy. For people with moderate disease, the decision about splenectomy should be based on the size of the spleen and the individual’s quality of life. Splenectomy is not recommended for people with mild HS. If possible, splenectomy should be delayed until age 6 or older. Minimally invasive (laparoscopic) splenectomy is recommended, as long as a trained surgeon and the correct equipment are available. Before splenectomy, the diagnosis of HS should be confirmed, since the risk of complication is higher in other conditions related to the red blood cells. After splenectomy, people are often given vaccinations and preventative antibiotics to reduce the risk of infection.
Surgical removal of part of the spleen (partial splenectomy) has been offered as an alternative to removal of the entire spleen (total splenectomy). Partial splenectomy may still reduce symptoms of HS without as much of an increase in risk of infection. Both total and partial splenectomy help normalize red blood cells, although total splenectomy appears to have a greater effect. The impact of partial splenectomy lasts at least 5 years. About 5 – 10% of people who had a partial splenectomy had symptoms develop again and 5% had a total splenectomy eventually.
Some people with HS also have surgery to remove their gallbladders (cholecystectomy). People who are having a cholecystectomy due to gallstones may also be recommended to have a splenectomy based on the severity of disease, as described above. However, in people who are having a splenectomy, cholecystectomy should only be done if there are symptomatic gallstones.
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Park SH, Park C-J, Lee B-R, et al. Screening For Hereditary Spherocytosis: EMA Binding Test and Flow Cytometric Osmotic Fragility Test Are Recommended, But Cryohemolysis Test Is Not Recommended. 2013;122(21):3425-3425.
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Bolton-Maggs PHB, Langer JC, Iolascon A, Tittensor P, King M-J. Guidelines for the diagnosis and management of HS – 2011 update. 2012;156(1):37-49.
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