Severe combined immunodeficiency (SCID) is a group of rare disorders caused by mutations in different genes involved in the development and function of infection-fighting immune cells. Infants with SCID appear healthy at birth but are highly susceptible to severe infections. The condition is fatal, usually within the first year or two of life, unless infants receive immune-restoring treatments, such as transplants of blood-forming stem cells, gene therapy, or enzyme therapy. More than 80 percent of SCID infants do not have a family history of the condition. However, development of a newborn screening test has made it possible to detect SCID before symptoms appear, helping ensure that affected infants receive life-saving treatments.

More than a dozen genes have been implicated in SCID, but gene defects are unknown in approximately 15 percent of newborn-screened SCID infants, according to an NIH-funded study. Most often, SCID is inherited in an autosomal recessive pattern, in which both copies of a particular gene—one inherited from the mother and one from the father—contain defects. The best-known form of autosomal recessive SCID is caused by adenosine deaminase (ADA) deficiency, in which infants lack the ADA enzyme necessary for T-cell survival. X-linked SCID, which is caused by mutations in a gene on the X chromosome, primarily affects male infants. Boys with this type of SCID have white blood cells that grow and develop abnormally. As a consequence, they have low numbers of T cells and natural killer cells, and their B cells do not function.

Symptoms of SCID occur in infancy and include serious or life-threatening infections, especially viral infections, which may result in pneumonia and chronic diarrhea. Candida (yeast) infections of the mouth and diaper area and pneumonia caused by the fungus Pneumocystis jirovecii also are common.

The SCID newborn screening test, originally developed at NIH, measures T cell receptor excision circles (TRECs), a byproduct of T-cell development. Because infants with SCID have few or no T cells, the absence of TRECs may indicate SCID. To confirm a SCID diagnosis, a doctor will evaluate the numbers and types of T and B cells present and their ability to function. Research supported by NIAID and other organizations has shown that early diagnosis of SCID through newborn screening leads to prompt treatment and high survival rates. SCID was added in 2010 to the U.S. Department of Health and Human Services’ Recommended Uniform Screening Panel for newborns. Today, all newborns in the United States are screened for SCID.

Hematopoietic (blood-forming) stem cell transplantation is the standard treatment for infants with SCID. Ideally, infants with SCID receive stem cells from a sibling who is a close tissue match. Transplants from matched siblings lead to the best restoration of immune function, but if a matched sibling is not available, infants may receive stem cells from a parent or an unrelated donor. These transplants are life-saving, but often only partially restore immunity. NIAID-supported research has shown that early transplantation is critical to achieving the best outcomes for SCID infants. Investigators analyzed data from 240 infants with SCID and found that those who received transplants before the age of 3.5 months were most likely to survive, regardless of the type of stem cell donor used.

Children who have SCID with ADA deficiency have been treated somewhat successfully with enzyme replacement therapy called PEG-ADA.

Studies also have shown that gene therapy can be an effective treatment for some types of SCID, including X-linked SCID. In gene therapy, stem cells are obtained from the patient’s bone marrow, the normal gene is inserted into the stem cells using a carrier known as a vector, and the corrected cells are returned to the patient. Early efforts to treat X-linked SCID with gene therapy successfully restored children’s T-cell function, but approximately one-quarter of the children developed leukemia two to five years after treatment. Scientists suspect that the vectors used in these studies activated genes that control cell growth, contributing to leukemia. Newer gene therapy strategies use modified vectors that appear effective and safe. NIAID researchers are using a novel gene therapy approach to successfully treat older children and young adults with X-linked SCID.

Severe combined immunodeficiencies (SCID) are a group of genetic conditions where a baby is born with a nonworking or poorly working immune system.

We need the immune system to fight infections. The immune system uses white blood cells called lymphocytes to fight against germs that invade the body. Lymphocytes include T cells, B cells, and natural killer (NK) cells.

In SCID, these T cells, B cells, or NK cells are absent or do not work correctly. There are several types of SCID. The type of SCID your baby has depends on which part of the immune system is problematic. The most common types of SCID are X-linked SCID and adenosine deaminase (ADA) deficiency.

X-linked SCID occurs mostly in boys and is also called “bubble-boy” disease. That is because a boy with the condition, David Vetter, lived in a plastic enclosure for 12 years before the availability of current treatments. In this condition, a protein needed to make normal T cells and NK cells is absent or nonworking. B cells are present, but they cannot work as well without help from the T cells. This type of SCID is in a category called T-B+NK- SCID, named after the types of lymphocytes affected.

ADA deficiency occurs when the enzyme adenosine deaminase is not made correctly. This enzyme helps remove toxic substances in cells that can destroy lymphocytes. Without working adenosine deaminase enzymes, these toxic products build up and kill all lymphocytes – T, B, and NK cells. This type of SCID is placed in the category T-B-NK- SCID.

There are also many other rare causes of SCID. In all causes of SCID, a change in the baby’s genes leads to similar problems with their immune system.

The most severe type of SCID is referred to as classic or typical SCID.

Another form of the condition is called leaky SCID. Unlike typical SCID, babies with leaky SCID may have small numbers of T cells, or only have T cells that do not work normally. This condition is also called Omenn syndrome.

If the immune system is absent or weak, your baby’s body has trouble fighting infections. They can get sick from germs that do not infect people with normal working immune systems, leading to the signs and symptoms of the condition. Without treatment and special protection from germs, SCID can lead to life-threatening illness or death.

It is estimated that fewer than 80 babies are born with the most common form of this condition each year in the United States.

Severe Combined Immunodeficiency is a severe, genetic condition of the immune system.

What is Severe Combined Immunodeficiency (SCID)?

Severe Combined Immunodeficiency (SCID) may be best known from news stories and a movie in the 1980s about David, the Boy in the Bubble, who was born without a working immune system. Caused by defects in any of several possible genes, SCID makes those affected highly susceptible to life-threatening infections by viruses, bacteria and fungi. Because David's brother had died of the disease, doctors immediately placed him into a plastic isolation unit to protect him from infections. He lived in such isolators for nearly 13 years. David died in 1984 following an unsuccessful bone marrow transplant, an attempt to provide him with the capacity to fight infections on his own and thus free him from the bubble.

Although a rare disease, SCID has been extensively studied over the past several decades because of the insights it provides into the workings of the normal human immune system. In addition, one form of SCID became the first human illness treated by human gene therapy in 1990, a process in which a normal gene was transferred into the defective white blood cells of two young girls to compensate for the genetic mutation. These pioneering patients are still alive and continue to participate in on-going studies by physicians at the National Human Genome Research Institute.

What do we know about the immune system and SCID?

Lymphocytes, a type of white blood cell, are made from blood forming precursors, or "stem," cells in the bone marrow. Some lymphocyte precursors move to the thymus gland, where they become T cells. Others remain in the bone marrow where they mature into B cells and natural killer cells. Each specialized type of cell is responsible for a particular immune response. Normally, T cells encourage other immune cells to respond to foreign substances as well as directly combat certain viral and fungal infections. B cells become antibody-producing cells. The antibodies attack foreign substances, or antigens, that mark invading viruses, bacteria and fungi.

Severe combined immunodeficiency, or SCID, is a term applied to a group of inherited disorders characterized by defects in both T and B cell responses, hence the term "combined." The most common type of SCID is called XSCID because the mutated gene, which normally produces a receptor for activation signals on immune cells, is located on the X chromosome. Another form of SCID is caused by a deficiency of the enzyme adenosine deaminase (ADA), normally produced by a gene on chromosome 20.

The classic symptoms of SCID include an increased susceptibility to a variety of infections, including ear infections (acute otitis media), pneumonia or bronchitis, oral thrush (a type of yeast that multiplies rapidly, creating white, sore areas in the mouth), and diarrhea. Because children with SCID experience multiple infections, they fail to grow and gain weight as expected (i.e., failure to thrive). Children with untreated SCID rarely live past the age of two.

How common is SCID?

There is no central record of how many babies are diagnosed with SCID in the United States each year, but the best estimate is somewhere around 40-100. So, SCID is a rare condition. On the other hand, researchers have no clear idea of how many babies are not diagnosed and die of SCID-related infections each year. The actual number of cases could be higher.

If a baby exhibits any of the following persistent symptoms within the first year of life, he or she should be evaluated for SCID or other types of immune deficiency syndromes:

• Eight or more ear infections

• Two or more cases of pneumonia

• Infections that do not resolve with antibiotic treatment for two or more months

• Failure to gain weight or grow normally

• Infections that require intravenous antibiotic treatment

• Deep-seated infections, such as pneumonia that affects an entire lung or an abscess in the liver

• Persistent thrush in the mouth or throat

• A family history of immune deficiency or infant deaths due to infections

What is XSCID?

X-linked severe combined immunodeficiency (XSCID) is caused by mutations in a gene on the X chromosome called IL2RG. This gene creates a key part of a receptor on the surface of a lymphocyte which, when activated by chemical messengers called cytokines, transmits information that directs lymphocytes to mature, proliferate and mobilize to fight infection. The defective part of the lymphocyte receptor is called the "common" gamma chain, because it is a common component of lymphocyte receptors for several types of cytokines, including the interleukin-2 (IL-2) receptor. Thus, it is a critical component for mobilizing the body's defenses against infection.

Because females have two X chromosomes, if they have a mutation that disrupts the IL2RG gene on one X chromosome, they still have a spare normal gene on the other X chromosome that can compensate for the mutation. Thus, they have normal immune systems. However, since males have only one X chromosome and one Y chromosome, they do not have a spare IL2RG gene. A male with a defect in his only IL2RG gene produces immune cells that are missing the ?c part of their receptors. Because the receptors cannot respond to stimulation, immune dysfunction and SCID sets in. XSCID affects only males and is the most common type of SCID. Therefore, the overall incidence of SCID is higher in males than in females.

What is ADA deficiency SCID?

Adenosine deaminase deficiency SCID, commonly called ADA SCID, is a very rare genetic disorder. It is caused by a mutation in the gene that encodes a protein called adenosine deaminase (ADA). This ADA protein is an essential enzyme needed by all body cells to produce new DNA. This enzyme also breaks down toxic metabolites that otherwise accumulate to harmful levels that kill lymphocytes. People afflicted with this disease often have to take antibiotics and supplemental infusions of antibodies to protect themselves from serious infections. They can also receive adenosine deaminase injections given once or twice a week. ADA SCID is lethal without treatment.

How is SCID diagnosed?

Early diagnosis of SCID is rare because doctors do not routinely count each type of white blood cell in newborns. As a result, the average age at which babies are diagnosed with SCID is just over six months, usually because of recurrent infections (see below) and failure to thrive. Blood tests for SCID typically reveal significantly lower-than-normal levels of T cells and a lack of germ-fighting antibodies. Even if B cells are present in the blood of SCID patients, they do a poor job of producing antibodies. Low antibody levels and lack of specific antibodies after vaccination or a natural infection are characteristic features of SCID.

Can SCID be detected before birth (prenatally)?

If the mutation leading to SCID in a family is known, an at-risk pregnancy can be tested by sequencing DNA from the fetus. However, SCID is so rare that prenatal testing of a baby with no family history is probably not justified because the test is so expensive.

Is SCID diagnosis in the newborn period possible and beneficial?

Newborns with SCID generally appear healthy because they are protected for a few weeks by antibodies produced by the mother and then transferred into the baby's blood. In addition, newborns have not been exposed to infections. Diagnosis and treatment before the onset of infections and the complications they cause in immune-compromised babies reduces costly hospitalizations and leads to better outcomes. Testing immediately after birth can be done, either by sequencing DNA if the family mutation is known or by counting the numbers of T and B cells and assessing their function. However, the current tests to confirm SCID must be applied to individual blood samples and take hours to prepare.

The high cost of current testing has prohibited newborn screening on a population-wide basis. To make screening for all newborns affordable, an automated screening method that could process hundreds of samples every day with minimal hands-on requirements would need to be developed. In addition, the results would have to be made quickly available to doctors for patient follow-up.

Is there effective treatment for SCID?

The most effective treatment for SCID is transplantation of blood-forming stem cells from the bone marrow of a healthy person. Bone marrow stem cells can live for a long time by renewing themselves as needed and also can produce a continuous supply of healthy immune cells. A bone marrow transplant from a tissue-matched sister or brother offers the greatest chance for curing SCID. However, most patients do not have a matched sibling donor, so transplants from a parent or unrelated matched donor are often performed. These latter types of transplant succeed less often than do transplants from a matched, related donor. All transplants done in the first three months of life have the highest success rate.

There are many different genetic causes of SCID. In nearly all cases, SCID is caused when one of several genes, which gives the body instructions for making parts of the immune system does not work.

X-linked SCID is caused by changes in the IL2RG gene. ADA deficiency is caused by changes in the ADA gene. There are several other genes associated with SCID that can be found by newborn screening. These types include those caused by changes in the RAG1, RAG2, DCLRE1C, NHEJ1, CD247, CD3E, CD3D, AK2, IL7RA, or PTPRC genes, among others.

In SCID, the immune system’s white blood cells, including T cells, B cells, or NK cells, are not made or do not work properly. Without these cells, especially T cells, the body cannot fight infections.

SCID is a genetic condition that is usually inherited. Babies inherit it from their biological (birth) parents. Rarely, a baby may spontaneously develop a genetic change associated with SCID, which is not inherited from either parent.

• The most common type of SCID, X-linked SCID, is inherited in an X-linked recessive pattern, which means babies inherit this condition on their X chromosome.
  • Girl babies have two X chromosomes, so only girls with two nonworking genes have SCID. Girls with one nonworking gene are carriers.
  • Boy babies only have one X chromosome, so boys with only one nonworking gene have SCID. This condition is more common in boys.
• Some types of SCID, including ADA deficiency, are autosomal recessive conditions. Babies inherit the condition when each parent passes down a nonworking gene to their baby. Only babies with two nonworking genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the gene, they have a 1 in 4 chance of having a child with SCID.
  • Carriers for SCID often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with SCID.
  • Parents who already have a child with SCID still have a 1 in 4 chance of having another child with SCID. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of SCID usually appear in the first few months after birth. SCID is often categorized into two types based on what signs and symptoms appear and how severe they are.

Signs of classic or typical SCID may include the following:

• High number of infections or infections caused by germs that do not affect healthy babies
• Infections that do not get better with antibiotic treatment
• Diarrhea
• Skin rashes
• Creamy white dots in the mouth or throat that do not get better (thrush)
• Poor weight gain or growth (failure to thrive)

Babies with leaky SCID have signs and symptoms similar to typical SCID.

Signs of leaky SCID may include the following:

• Itchy, red skin
• Diarrhea
• Hair loss
• Enlarged liver and spleen
• Swollen lymph nodes
• Autoimmune problems

A diagnosis of SCID may be suspected if a baby shows any of the following persistent symptoms within the first year of life:

• Eight or more ear infections
• Two or more cases of pneumonia
• Infections that do not resolve with antibiotic treatment for two or more months
• Failure to gain weight or grow normally
• Infections that require intravenous (IV) antibiotic treatment
• Deep-seated infections, such as pneumonia that affects an entire lung or an abscess in the liver
• Persistent thrush in the mouth or throat
• A family history of immune deficiency or infant deaths due to infections

A diagnosis can be confirmed by blood tests. Blood tests show significantly lower-than-normal levels of T cells and antibodies.

Since there are other conditions that can result in lower-than-normal numbers of the different types of lymphocytes, the most important tests are those of T-cell function by placing blood lymphocytes in culture tubes, and treating them with various stimulants. Normal T-lymphocytes react to these stimulants by undergoing cell division. In contrast, lymphocytes from patients with SCID usually do not react to these stimuli.

Immunoglobulin levels are usually very low in SCID. Most commonly (but not always), all immunoglobulin classes are depressed (IgG, IgA, IgM and IgE).

The diagnosis of SCID can also be made before the baby is born if there has been another infant in the family with the disorder and if the gene defect has been identified. If genetic analysis had been completed on the infant in the family with SCID, a diagnosis can be determined during subsequent pregnancies. This can be done by molecular testing of cells from a chorionic villous sampling (CVS) or from an amniocentesis, where a small amount of amniotic fluid (which contains fetal cells) is removed.

Early diagnosis, before the infant has had a chance to develop any infections, is very valuable since bone marrow transplants given in the first three months of life have a 94% success rate. In fact, screening newborns to detect SCID soon after birth has been made possible because of recent scientific advances. Approximately half of the babies born in the U.S. are now being screened for SCID.

Newborn screening for SCID is done using a small amount of blood collected from your baby’s heel. During screening, a machine measures how many small pieces of DNA, called T cell receptor excision circles, (TRECs) are in your baby’s blood. The body produces TRECs when it is developing the T cells of the immune system. Babies without an immune system, or one that does not work as it should, will have little or no TRECs. These babies might have SCID.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for SCID is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has SCID. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood tests
• Genetic tests using a blood sample or other sample (collected from the mouth or skin, if needed)

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems in the first few months after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition do occur. Screening samples collected from babies who were born early (premature) or who are very sick (in the newborn intensive care unit, or NICU) for other reasons can have false-positive results. This screening can also pick up other conditions that affect the immune system.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

Treatment options for this condition are listed below. It is important to talk to your health care provider about which treatment(s) are best for your baby.

The goal of treatment is to prevent the health problems caused by this condition. Treatments may include the following:

• Isolation (avoiding infections/germs)
• Antibody treatment (also called immunoglobulin replacement therapy)
• Antimicrobial therapy (antibiotics, antifungals, antiviral medications)
• Bone marrow transplant to help replace and grow an immune system
• Thymus transplant (for specific forms of SCID)
• Gene therapy (for certain forms of SCID, e.g., X-linked SCID and ADA-SCID).

Children who receive early and ongoing treatment for SCID are less likely to have life-threatening infections and illnesses and have better long-term survival. Children who receive bone marrow, thymus transplants, or gene therapy can lead healthier lives.

At a Glance

• Gene therapy restored immune system function to children with an inherited immune disorder with fewer side effects than existing therapies.

• The therapy could be a safe and effective treatment for this rare and life-threatening condition.

Children born with a rare genetic disorder called severe combined immunodeficiency (SCID) cannot produce the immune cells that fight infections. Without treatment, they usually die from infections by age two.

One cause of SCID is a mutation in the gene for an enzyme called adenosine deaminase (ADA). Replacing the defective ADA with injections of the normal enzyme once or twice a week can treat the condition, but it doesn’t restore full immune function and must be taken for life. Patients also need to have periodic infusions of antibodies derived from human blood plasma. A more long-term treatment involves transplanting blood-forming stem cells from a healthy donor. Unfortunately, only about 20% of patients have compatible donors available.

A potential alternative to transplantation is gene therapy. This involves removing some of the patient’s own stem cells, adding a normal copy of the ADA gene, and then returning the modified cells to the patient. Highly engineered viruses, rendered harmless, are used to introduce the gene. But the type of virus used in previous gene therapy approaches led to serious side effects, including leukemia.

In a new study, a team led by Donald Kohn at the University of California, Los Angeles tested a different type of engineered virus, designed to reduce side effects, for introducing the gene. Researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Human Genome Research Institute (NHGRI) participated in the research, and NIAID and NIH’s National Heart, Lung, and Blood Institute (NHLBI) provided financial support. The results appeared in the New England Journal of Medicine on May 11, 2021.

The researchers treated 50 patients with ADA-SCID in the United States and United Kingdom. The U.S. patients were followed for two years after treatment and the U.K. patients for three years. All patients survived through the end of the follow-up period. Only one U.S. patient and one U.K. patient had to resume enzyme-replacement therapy because the modified stem cells didn’t take hold. The ADA in the patients appeared to function effectively. Notably, all U.K. patients and 90% of U.S. patients were able to stop antibody-replacement therapy by the end of the studies.

Although some side effects occurred in all patients, most were mild to moderate. A low dose of chemotherapy was used to help the modified stem cells establish themselves. Most side effects could be attributed to this rather than the gene therapy itself. The researchers didn’t find any cases of the virus replicating in the patients. They also didn’t see excess immune cell proliferation that could lead to cancer. Nor were there any cases of the patient’s immune system attacking its own cells or the transplanted cells.

These results suggest that gene therapy could be a safe and effective treatment for ADA-SCID. Although the study size was small, the survival rates were higher than for stem cell transplantation. Ten of the U.S. patients were treated with cells that had been frozen and later thawed. Further trials of this cryopreservation procedure are now underway. If successful, it could increase access to treatment by allowing modified stem cells to be shipped to local hospitals.

“These findings suggest that this experimental gene therapy could serve as a potential treatment option for infants and older children with ADA-SCID,” says NIAID Director Dr. Anthony S. Fauci. “Importantly, gene therapy is a one-time procedure that offers patients the hope of developing a completely functional immune system and the chance to live a full, healthy life.”

—by Brian Doctrow, Ph.D.