NORD gratefully acknowledges MA Bender, MD, PhD, Department of Pediatrics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington, for assistance in the preparation of this report.
Sickle cell disease (SCD) is a rare blood disorder that is inherited in an autosomal recessive manner. It is characterized by the presence of sickle, or crescent-shaped, red blood cells (erythrocytes) in the bloodstream. These crescent-shaped cells are stiff and sticky and interact with other cells and the blood clotting system to block blood flow in the very tiny blood vessels (capillaries) of the peripheral blood system (blood vessels outside of the heart). This prevents the normal flow of nutrition and oxygen (as red blood cells are responsible for carrying oxygen throughout the body).
Common symptoms associated with SCD include excruciating bone pain, chest pain, severe infections (primarily in children), low levels of circulating red blood cells (anemia) and yellowing of the skin (jaundice). The blocked blood flow can also cause severe organ damage including stroke. SCD has several recognized forms including sickle cell anemia, sickle cell hemoglobin C disease, and sickle cell / beta-thalassemia disease.
Hemoglobin is an iron-rich protein contained in red blood cells and is responsible for carrying oxygen from the lungs to the rest of the body. In SCD, the symptoms stem from the abnormal hemoglobin in the red blood cells. The abnormal hemoglobin causes the red blood cells to be sickle-shaped which triggers a series of events leading to fragile red blood cells and blocking blood flow.
The most common signs and symptoms of SCD are associated with low red blood cells (anemia) and pain. The most common symptom of anemia is feeling tired and weak (fatigue). Sickle cell pain episodes can occur suddenly and is typically in bones and the abdomen, but can occur almost anywhere. The pain can last for days to over a week (acute) or continue long-term (chronic). Damage can occur to most parts of the body including the brain, lung, kidneys, and joints. SCD can cause yellow eyes (jaundice) from the breakdown of blood. Signs in infants can include swollen and painful hands and/or feet (dactylitis), irritability, crying, and severe infections.
In patients with SCD, the spleen can become enlarged (splenomegaly) as it traps red blood cells that should be in the bloodstream. The spleen functions to filter out abnormal red blood cells and fights some infections such as the bacteria that cause strep throat. Damage to the spleen leads to decreased ability to fight some typically mild infections that can become life-threatening in SCD.
Acute chest syndrome can occur if an infection or sickled cells damages the lungs. This is a life-threatening complication of SCD. Sometimes people can’t tell they have it but other times people can have chest pain, difficulty breathing or fever. Additional complications of SCD include stroke, which can occur in children as young as 2 years. Boys and men with sickle cell disease may experience painful, prolonged erections (priapism) at any age.
The signs and symptoms of SCD vary from patient to patient, and some patients have more mild symptoms while others may have more severe symptoms requiring hospitalization. SCD is present at birth; however, most infants do not show any signs until four months of age and many do not show signs until several years of age. The symptoms typically begin in the first three years of life. Sometimes the first suggestion of SCD is a painful swelling of an infant’s hands or feet (dactylitis). The extreme pain episodes are often triggered by something such as getting cold, becoming dehydrated, infection, over doing it, or trauma. Children with SCD may grow slowly and reach puberty later.
As people with SCD age, other additional complications become more common. Pulmonary hypertension can develop due to damage to the small blood vessels and air sacs in the lungs. This can cause decreased ability to exercise, shortness of breath and tiredness. Leg sores that are often hard to heal can occur; damage to the retina can occur causing eye problems. Damage to the joints (avascular necrosis) and the loss of bone may cause pain in the joints when walking, standing and/or lifting. Kidney damage can occur and gallstones are often present.
There are many forms of SCD. The most common severe form is S/S which some call sickle cell anemia. Some forms, like sickle beta-zero thalassemia are just as severe as the S/S form. Sickle beta-plus thalassemia and sickle cell hemoglobin C disease are usually less severe. Diagnosing exactly what form of SCD someone has is important and there is a lot of confusion about the different forms.
SCD is caused by mutations in the hemoglobin beta (HBB) gene and is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same altered gene for the same trait from each parent. If an individual receives one normal gene and one 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 altered 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 and be genetically normal for that particular trait is 25%.
In SCD this is more complicated. People who receive the sickle mutation from each parent (S/S) have the disease. Some people with SCD only get the sickle mutation from one parent, but have a different mutation from the other parent. This can lead to forms of SCD such as sickle beta- thalassemia and sickle cell hemoglobin C disease. Diagnosing exactly what form of SCD someone has is important and there is a lot of confusion about the different forms.
People who inherit only one HBB gene mutation are said to have “sickle cell trait.” These people are generally symptom-free carriers who can pass the gene on to their offspring. Some people with sickle cell trait may have some medical complications and show some symptoms.
The frequency of SCD varies from country to country. SCD affects 0.6 percent of the African American population in the United States (approximately 100,000 cases in the United States). It is also common in people of Hispanic decent, from India, Central America and the Arabian Peninsula, but can occur in people of any background. SCD affects approximately one in every 300 – 500 African American newborns. The sickle cell trait is present in approximately 40 percent of the general population in some areas of Africa. The incidence of sickle cell trait in Americans of African descent is 9 percent.
Mutations in the HBB gene are common in people from African, Mediterranean, Middle Eastern, and Indian ancestry and in people from the Caribbean and parts of Central and South America, but can be found in people of any ethnicity.
All newborns born in the US are tested for SCD by electrophoresis and or high pressure liquid chromatography. Molecular genetic testing for mutations in the HBB gene is also available.
Prevention is the best treatment. Patient and family education, medicines such as hydroxycarbamide, avoiding triggers, early intervention, and testing to pick up developing complications early so they can be treated before they are severe can significantly improve outcomes.
While very few patients with SCD have the opportunity to be cured, early referral of newborns to specialty centers can provide education and resources that help control symptoms and dramatically improve quality of life for patients. People with SCD should have regular medical checkups where education on preventing complications has a tremendous benefit on health. Teaching families about how to carefully monitor children for fevers while at home, giving low dose penicillin and immunizations, and assuring families have the information and ability to reach a hospital when ill dramatically decreases severe infections and death. Many simple lifestyle activities can be done to support health and minimize pain and other complications. These include remaining hydrated, not getting too hot or cold, getting exercise, deep breathing, not getting fatigued and avoiding trauma.
It is important to try to avoid sickle cell pain as mentioned above. Once pain occurs, it is important to use many approaches to treat the severe pain in SCD, not just medications. Reversing triggers of pain is key, thus hydration, remaining warm, walking around and deep breathing are very important. Distraction can be a huge help, as are approaches such as massage, acupuncture, and hypnosis. Pain-relieving medications, such as non-steroidal anti-inflammatory agents and opiate analgesics may be administered during painful episodes.
Blood transfusions can be used for many reasons such as very severe anemia, preparing for surgery, and to reduce the risk of, or treat stroke. In some people, surgery may be necessary because of damage to specific organs such as gall bladder surgery (cholecystectomy) to remove gallstones.
Stem cell transplant can provide a cure for patients but the chance of success and potential risks vary depend on many factors.
Hydroxycarbamide (hydroxyurea) has been approved by the Food and Drug Administration (FDA) for the treatment of SCD and is recommended for most patients with the S/S and sickle beta-zero thalassemia forms of SCD. It should be offered to children with these forms by 9 months of age. Hydroxyurea helps stimulate the body to make fetal hemoglobin, the type of hemoglobin that newborns have and lowers white blood cells that can contribute to slowing blood flow. As a result, hydroxycarbamide can decrease pain, improve the anemia, decrease hospitalizations and lung problems, and increase lifespan.
In 2017, the FDA approved Endari (L-glutamine) for patients age five years and older with SCD to reduce severe complications associated with this condition. Endari is manufactured by Emmaus Medical Inc.
Folic acid is used to assure the body can make enough red blood cells.
Genetic counseling is recommended for affected individuals and their families.
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Sickle Cell Disease. Genetics Home Reference. Available at: http://ghr.nlm.nih.gov/condition/sickle-cell-disease Reviewed August 2012. Accessed September 21, 2017.
Sickle Cell Anemia. National Heart, Lung, and Blood Institute. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/sca Updated: August 10 2017. Accessed September 21, 2017.
Sickle Cell Disease (SCD). Centers for Disease Control and Prevention (CDC). Available at: https://www.cdc.gov/ncbddd/sicklecell/index.html Accessed September 21, 2017.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:603903; Available at http://omim.org/entry/603903 Last Update: 05/12/2017. Accessed September 21, 2017.
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