What is sickle cell disease?
Sickle cell disease is an inherited blood disorder. Normal red blood cells are smooth and flexible discs, like the letter O, enabling them to move easily through your child’s blood vessels. In contrast, sickle cells are stiff, sticky, and often shaped like the letter C. Sickle cells tend to cluster together and to the lining of blood vessels, making it difficult for them to move through small blood vessels. These clusters can create blockages in your child’s small blood vessels, stopping the movement of healthy, oxygen-carrying blood. This blockage decreases oxygen delivery to the tissues, which can cause pain and organ dysfunction and is what causes the majority of the complications of the disease.
Sickle cell gene therapy and boosting fetal hemoglobin: A 75-year history
The first gene editing therapy for sickle cell disease to be approved by the Food and Drug Administration has deep roots at Boston Children’s Hospital.
The spleen, which helps filter bacterial infections from the blood and acts as the recycle center for old red blood cells, tends to destroy the misshapen sickle cells faster than normal red blood cells. Sickle cells only live for about 14 days, while normal red blood cells can live up to 120 days. This leads to a chronic lack of oxygen-carrying red cells in the blood, called anemia. Sickle cells can also damage your child’s spleen, increasing the risk of certain potentially life-threatening bacterial infections.
Millions worldwide suffer complications from sickle cell disease and nearly 300,000 infants with sickle cell disease are born each year. Approximately 2 million African-Americans, or 1 in 12, are "carriers" of the sickle mutation (called sickle cell trait). About 100,000 people in the United States have sickle cell disease. It mostly affects children of African descent, Hispanics, and Caribbean ancestry, but also is found in those with Middle Eastern, Indian, Latin American, and Mediterranean heritage. The Global Health Initiative at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center is working to improve survival for children with sickle cell disease around the world, including programs to establish newborn screening for sickle cell disease and developing research partnerships in Liberia and Haiti.
What are the different types of sickle cell disease in children?
All children with sickle cell disease have inherited sickle cell trait (HbAS) from at least one parent. People with sickle cell trait have one copy of the HbS gene and one copy of the normal hemoglobin A gene (HbA). Sickle cell trait is not a form of sickle cell disease, although in rare circumstances, sickle cell trait can become symptomatic. People with sickle cell trait may pass on the HbS gene to their children.
There are several different types of sickle cell disease that differ in symptoms and severity. The type of sickle cell disease depends on the specific gene variant that your child has inherited.
Sickle cell anemia (HbSS)
- The child has two copies of the HbS gene, one inherited from each parent.
- This is the most common and most severe form of sickle cell disease.
- A variety of symptoms and complications of sickle cell disease occur.
- Severe, chronic anemia is present.
Sickle cell with hemoglobin C disease (HbSC)
- The child has one HbS gene and one defective hemoglobin C gene (HbC).
- A more mild to moderate anemia is typical.
- All complications of sickle cell disease may occur but tend to be a milder degree.
Hemoglobin S-β-thalassemia
- This comes in two forms: HbSβ0 and Hbβ+ thalassemia.
- The child has one HbS gene and one β thalassemia gene.
- The degree of anemia is varied depending on the specific genetic type.
- Children may experience a broad range of sickle cell symptoms and disease severity. HbSβ0 thalassemia is very similar to HbSS. Hbβ+ thalassemia severity is varied but usually mild.
Other forms of sickle cell disease (compound heterozygotes), including HbSE, HbSO, and HbSD
- The child has one HbS gene and another abnormal hemoglobin gene.
- Symptoms vary depending on the specific genetic defect.
Sickle Cell Disease | Symptoms & Causes
What are the symptoms of sickle cell disease in children?
The severity of the symptoms of sickle cell disease in children can vary greatly depending on the specific genetic type and even within those of the same type. Each child may experience symptoms differently, and symptoms can be very difficult to predict. Symptoms and complications of sickle cell disease may include the following.
Anemia
Anemia is the most common feature of all the sickle cell diseases. Anemia may delay normal growth and development and decrease energy and endurance.
Pain crisis (also called vaso-occlusive crisis)
This occurs when the flow of blood is blocked to an area because the sickle-shaped cells have become stuck in the blood vessel. Pain can occur anywhere but most often occurs in the bones of the arms, legs, chest, and spine. Painful swelling of the small bones of the hands and feet (dactylitis) can occur in infants and toddlers. Priapism results from sickling that occurs in the penis. This results in a painful and unwanted erection. Any interruption in blood flow to the body can result in pain, swelling, dysfunction, and possible death of the surrounding tissue not receiving adequate blood and oxygen.
Acute chest syndrome (ACS)
This occurs when sickle-shaped cells stick together and block the flow of oxygen in the vessels in the lungs. It can be life-threatening and is the leading cause of death in children and adults with sickle cell disease. ACS can be triggered by asthma crisis, infection (viral or bacterial), or pain (particularly in the chest) and can progress rapidly to respiratory failure. It resembles pneumonia and includes fever and breathing symptoms such as cough or difficulty catching breath. ACS often occurs suddenly, when the body is under stress from infection, fever, or dehydration, and multiple episodes can cause permanent lung damage.
Bacterial infection and sepsis
In most children with sickle cell disease, by toddlerhood, the spleen becomes scarred and permanently damaged and no longer has full function. The spleen is important in the body’s defense against serious bacterial infections; therefore, children with sickle cell disease are at risk for life-threatening bacterial infections. Fever (>38.5⁰C or 101.5⁰F) is a symptom that must be evaluated immediately to rule out a life-threatening bacterial infection.
Splenic sequestration (pooling)
Sickle cells can block the exit of blood from the spleen, resulting in pooling of sickle-shaped cells in the spleen and causing a sudden worsening of the anemia. The spleen becomes enlarged and painful from the increase in trapped blood volume. It can be life threatening if not treated promptly. A severe episode of sequestration requires surgical removal of the spleen.
Stroke
This is a sudden and severe complication that can occur in children with sickle cell disease. Sickle-shaped cells can block the major blood vessels that supply the brain with oxygen. Interruption in the flow of blood and oxygen to the brain can result in devastating damage to the brain. Symptoms of a stroke can include weakness, particularly on one side of the body; slurred speech; seizure; confusion; dizziness or loss of coordination; or a severe headache. Having had one stroke, a child is much more likely to have more strokes and requires preventative therapy with chronic repeated transfusion for life.
Jaundice
Jaundice is a common sign and symptom of sickle cell disease. Sickle red blood cells are destroyed prematurely in the spleen. The recycling of sickle hemoglobin from these cells produces increased levels of the yellow bilirubin protein that discolors the skin and eyes. Chronic high bilirubin levels can lead to gallstone formation.
Other
Any and all major organs are also affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints can suffer damage from the abnormal function of the sickle cells and their inability to flow through the small blood vessels correctly. Problems may include:
- Leg ulcers
- Bone/joint damage
- Kidney damage and loss of body water in the urine
- Eye and retinal damage
What causes sickle cell disease in children?
The following are the most common ways a child can develop sickle cell disease:
- If both parents have sickle cell trait, each of their children will have a 25 percent chance of having sickle cell disease.
- If one parent has sickle cell disease and the other has sickle cell trait, each of their children will have a 50 percent chance of having sickle cell disease and a 50 percent chance of having sickle cell trait.
- If one parent has sickle cell disease and the other does not, all of their children will have sickle cell trait, but none of them will have sickle cell disease.
Sickle Cell Disease | Diagnosis & Treatments
How is sickle cell disease diagnosed in children?
The first step in treating your child is providing an accurate and complete diagnosis. Early diagnosis of sickle cell disease is essential in providing proper preventative treatment for some of the devastating potential complications. Sickle cell disease can be identified by the following tests:
- Review of newborn screening results
- Hemoglobin electrophoresis
- Complete family history
- Additional blood tests
In addition, using genetic testing, we are able to identify the specific type of sickle cell disease as well as your child’s unique genetic variations.
Newborn hemoglobin electrophoresis screening
Certain newborn screening tests are done within the first few days of life on every baby born in the U.S. to detect serious, life-threatening diseases. A hemoglobin electrophoresis is a newborn screening blood test that can determine if your child is a carrier of sickle cell trait or has sickle cell disease.
Manny: Hoping research will help others with sickle cell disease
In 2018, Manny Johnson was our first patient to receive gene therapy for sickle cell disease at Boston Children’s, and he’s been symptom-free ever since.
What are the treatment options for sickle cell disease in children and teens?
Gene therapy
Several types of gene therapy are now available for teens with sickle cell disease. All involve collecting a person’s own blood stem cells, treating them with gene therapy in a special facility, and then giving them back through an IV infusion.
- CASGEVY™, approved by the Food and Drug Administration in 2023, draws on decades of research at Dana Farber/Boston Children's. It uses CRISPR gene editing to silence a gene in red blood cells, called BCL11A. This enables the body to produce a fetal form of hemoglobin, which does not cause cells to sickle. People age 12 and older are eligible. Boston Children's is a qualified treatment center for CASGEVY™.
- LYFGENIA™, also approved by the FDA in 2023, uses a delivery vehicle (vector), consisting of a harmless virus, to introduce a healthy copy of the beta-globin gene into people’s blood stem cells. The treated cells are returned to the body and begin making red blood cells with healthy non-sickle hemoglobin. Boston Children's is a qualified treatment center for LYFGENIA™.
- Gene transfer: Boston Children's also offers two additional gene therapy treatments for sickle cell disease in a clinical trial setting. Both use a harmless virus to deliver the treatment into blood stem cells.
- Base editing: Boston Children’s is part of a Phase 1/2 trial of base editing in patients age 18 to 35 with severe sickle cell disease. This highly targeted type of gene editing uses enzymes to chemically change one “letter” of the genetic code to another, in this case changing an A to a G (adenosine to guanine). This directly stimulates fetal hemoglobin production.
All of these approaches involve collecting blood stem cells from the patient and treating them in a special laboratory. The gene-modified cells are then given back to the patient via an intravenous (IV) infusion. Contact gene.therapy@childrens.harvard.edu for more information about gene therapy.
Prevention of bacterial infections and sepsis
Most children with sickle cell disease must:
- Take preventative dosing penicillin until at least age 5
- Complete all routine childhood vaccinations and additional sickle cell specific vaccinations
- Maintain vigilance regarding fevers and signs of infection
Hydroxyurea therapy
Hydroxyurea is an oral medication that causes the body to produce fetal hemoglobin (HbF), a type of hemoglobin normally found only in fetuses and very young children.Increasing the healthy fetal hemoglobin can significantly reduce the side effects and complications of sickle cell disease.
Transfusion therapy
Blood transfusions may be given acutely in order to treat severe anemia, acute chest syndrome, and other life-threatening complications of sickle cell disease. Children with sickle cell disease may receive chronic blood transfusions to prevent complications such as stroke.
Iron chelators
Children with sickle cell anemia who require chronic red blood cell transfusions to prevent a stroke gradually become iron overloaded. Without removal of this iron, it can build up and become toxic to several vital organs. Iron can be removed from the body by medications called chelators. Children may take chelators orally or by injection in order to remove excess iron from the body. Your child's physician may also recommend specific treatments based on the symptoms your child experiences.
For anemia
Prevention:
- Folic acid
- Hydroxyurea
Treatment:
- Blood transfusion
For pain
Prevention:
- Drinking plenty of water daily (8 to 10 glasses)
- Avoiding dehydration
- Hydroxyurea medication to prevent painful events
Treatment:
- Receiving fluids intravenously
- Pain medications such as non-steroidal anti-inflammatories and opioids
For acute chest syndrome (ACS)
Prevention:
- Hydroxyurea
- Incentive spirometry (deep breathing)
Treatment:
- Broad spectrum antibiotics
- Blood transfusions to dilute HbS with normal hemoglobin
For splenic sequestrations
- Blood transfusions to dilute HbS with normal hemoglobin and promote "release" of blood trapped in the spleen
- Penicillin for those who have their spleen surgically removed
For stroke
- Blood transfusion
Stem cell transplant
Right now, the only cure for sickle cell disease is stem cell transplant (also called bone marrow transplant) — the transplantation of normal blood stem cells from another person (the ”donor”) to your child. In sickle cell disease, the best transplant outcomes are almost always when the donor is a healthy sibling with compatible stem cells. The stem cells replace the sickle blood stem cells and restore normal blood production in children with sickle cell disease.
The first step is to determine if the patient has a compatible full-sibling donor. This is done with a blood test or a swab of the cheek.
How we care for sickle cell disease
Dana-Farber/Boston Children's Cancer and Blood Disorders Center is an international leader in improving treatment and quality of life for children affected by sickle cell disease. We treat sickle cell anemia (HbSS), sickle cell with hemoglobin C disease (HbSC), hemoglobin S-beta-thalassemia (HbSβ0 and Hbβ+thalassemia), and less common compound forms, including HbSD, HbSO, and HbSE.
Through our Sickle Cell Disease Program, children with sickle cell disease have access to world-renown pediatric hematologists, top-rated nursing care, and the latest treatment options including hydroxyurea and stem cell transplantation. We are also one of the few centers in the nation using a new type of technology, called PreciseType, to precisely match blood donors to sickle cell patients who need blood transfusions. PreciseType allows our doctors to more precisely type the patient’s blood groups and decreases the risk of developing antibodies to the transfused donor blood.
