Severe combined immunodeficiency

Definition

SCID, or severe combined immunodeficiency, is a group of rare, life-threatening diseases present at birth that impair the immune system. Without a healthy immune system the body cannot fight infections and individuals can easily become seriously ill from common infections.

Description

SCID is one type of Primary Immunodeficiency Diseases (PID) and is considered the most severe. There are approximately 70 forms of PID. Primary immunodeficiency diseases are where a person is missing a component of the immune system—either an organ or cells of the immune system. Some deficiencies are deadly, while others are mild.

SCID is also known as the "boy in the bubble" syndrome, because living in a normal environment can be fatal. SCID initially was called Swiss agammaglobulinemia because it was first described in Switzerland in 1961. Any exposure to germs can pose a risk for infection, including bacterial, viral, and fungal. In the first few months of life, children with SCID become very ill with infections such as pneumonia (infection of the lungs which prevents oxygen from reaching the blood, making breathing difficult), meningitis (infection of the covering of the brain and spinal cord), sepsis (infection in the bloodstream) and chickenpox, and can die within the first year of life, since their immune system is unable to fight off these infections.

Children with SCID do not respond to medications like other children because their immune system does not function properly. They may also not have a developed thymus gland. Medication usually stimulates a person's immune system to fight infection, but in the case of SCID, the immune system is unable to respond. The immune system is a complex network of cells and organs that protect the body from infection. The thymus and lymphatic system (lymph nodes and lymphatic vessels) house and transport two very important cells that fight infection: the B and T cells. The bone marrow (center of bones) produces cells that become blood cells as well as cells for the immune system. One type of cell, called lymphocytes or white blood cells, mature in the bone marrow to form "B" cells, while others mature in the thymus to become "T" cells. B and T cells are the two major groups of lymphocytes that recognize and attack infections. Children with SCID have either abnormal or absent B and T cells.

Other infections can be seen in children with SCID including skin infections, yeast infections in the mouth and diaper area, diarrhea, and infection of the liver. Children with SCID fail to gain weight and grow normally. Treatment for SCID is available, however, many children with SCID are not diagnosed in time and die before their first birthday.

A diagnosis of SCID, besides being painful, frightening, and frustrating, needs to be made quickly since common infections can prove fatal. In addition, permanent damage can result in the ears, lungs, and other organs.

Genetic profile

SCID is a group of inherited disorders with about half inherited by a gene on the X chromosome called IL2RG, 15% inherited by an autosomal recessive gene called ADA, and the remaining 35% caused by either an unknown autosomal recessive gene or are the result of a new mutation.

Genetic information is carried in tiny packages called chromosomes. Each chromosome contains thousands of genes and each gene contains the information for a specific trait. All human cells (except egg and sperm cells) contain 23 pairs of chromosomes for a total of 46 chromosomes. One of each pair of chromosomes is inherited from the mother and the other is inherited from the father. SCID is usually inherited in one of two ways: X-linked recessive or autosomal recessive. Autosomal recessive means that the gene for the disease or trait is located on one of the first 22 pairs of chromosomes, which are also called autosomes. Males and females are equally likely to have an autosomal recessive disease or trait. Recessive means that two copies of the gene are

necessary to express the condition. Therefore, a child inherits one copy of the gene from each parent, who are called carriers (because they have only one copy of the gene). Since carriers do not express the gene, parents usually do not know they carry the SCID gene until they have an affected child. Carrier parents have a 1-in-4 chance (or 25%) with each pregnancy, to have a child with SCID.

The last pair of human chromosomes, either two X's (female) or one X and one Y (male)—determines gender. X-linked means the gene causing the disease or trait is located on the X chromosome. The term "recessive" usually infers that two copies of a gene—one on each of the chromosome pair—are necessary to cause a disease or express a particular trait. X-linked recessive diseases are most often seen in males, however, because they only have a one X chromosome. Therefore, if a male inherits a particular gene on the X, he expresses the gene, even though he only has a single copy of it. Females, on the other hand, have two X chromosomes, and therefore can carry a gene on one of their X chromosomes yet not express any symptoms. (Their second X chromosome works normally). A mother usually carries the gene for SCID unknowingly, and has a 50/50 chance with each pregnancy to transmit the gene. If the child is male, he will have SCID; if the child is female, she will be a carrier for SCID like the mother.

New mutations—alterations in the DNA of the gene—can cause disease. In these cases, neither parent has the disease-causing mutation. This may occur because the mutation in the gene happened for the first time only in the egg or sperm for that particular pregnancy. New mutations are thought to happen by chance and are therefore referred to as "sporadic", meaning, by chance.

Demographics

It is estimated that about 400 children a year are born with some type of primary immunodeficiency disease. Approximately one in 100,000 children are born with SCID each year, regardless of the part of the world the child is from, or the ethnic background of the parents. This disease can affect both males and females depending on its mode of inheritance .

Signs and symptoms

Babies with SCID fail to thrive, are frail, and do not grow well. They have numerous, serious, life-threatening infections that usually begin in the first few months of life. Because they do not respond to medications like other children, they may be on antibiotics for 1–2 months with no improvement before a physician considers a diagnosis of SCID. The types of infections typically include chronic (developing slowly and persisting for a long period of time) skin infections, yeast infections in the mouth and diaper area, diarrhea, infection of the liver, pneumonia, meningitis, and sepsis. They can also have serious sinus and ear infections, as well as a swollen abdomen. Sometimes deep abscesses occur, which are pockets of pus that form around infections in the skin or in the body organs.

Diagnosis

About half of children who see a doctor for frequent infections are normal; another 30% may have allergies, 10% have some other type of serious disorder, and 10% have a primary or secondary immunodeficiency. A diagnosis of SCID is usually made based on a complete medical history and physical examination, in addition to multiple blood tests and chest x rays. The gene in X-linked recessive SCID is called the interleukin receptor gamma chain gene or IL2RG. The autosomal recessive forms of SCID are caused by a variety of different genes; one of the more common is called the adenosine deaminase gene or ADA. Since newborns do not routinely have a test to count white blood cells, SCID is not usually suspected and then diagnosed until the child develops their first infection. A pattern of recurrent infections suggests an immunodeficiency.

Once a couple has had a child with SCID, and they have had the genetic cause identified by DNA studies (performed from a small blood sample), prenatal testing for future pregnancies may be considered on a research basis for some types of SCID. (Note that prenatal testing may not be possible if a mutation cannot be identified). Prenatal diagnosis is available via either CVS (chorionic villus sampling) or amniocentesis . CVS is a biopsy of the placenta performed in the first trimester or the first 12 weeks of pregnancy under ultrasound guidance. Ultrasound is the use of sound waves to visualize the locations of the developing baby and the placenta. The genetic makeup of the placenta is identical to the fetus (developing baby) and therefore the presence or absence of one of the SCID genes can be determined from this tissue. Amniocentesis is a procedure performed under ultrasound guidance where a long thin needle is inserted into the mother's abdomen, into the uterus, to withdraw a couple of tablespoons of amniotic fluid (fluid surrounding the developing baby) to study. The SCID gene can be studied using cells from the amniotic fluid. Other genetic tests, such as a chromosome analysis, may also be performed on either a CVS or amniocentesis. A small risk of miscarriage is associated with amniocentesis and CVS.

Treatment and management

The best treatment for SCID is a bone marrow transplant (BMT). A bone marrow transplant involves taking cells that are normally present in bone marrow (the center of bones that produce and store blood cells), and giving them back to the child with SCID or to another person. The goal of BMT is to infuse healthy bone marrow cells into a person after their own unhealthy bone marrow has been eliminated. BMT helps to strengthen a child with SCID's immune system.

Other treatment for SCID includes treating each infection promptly and accurately. Injections are also available to help boost a child's immune system.

In the year 2000, gene therapy was first reported to be successful in two French patients with SCID. The idea behind gene therapy is to replace an abnormal gene with a normal copy. In SCID, bone marrow is removed to isolate the patients' stem cells. Stem cells are special cells in the bone marrow that produce lymphocytes. In a laboratory, the normal gene is added to the abnormal stem cells. The genetically altered stem cells now have the normal gene and are transplanted back into the patient. Once the functioning stem cells with the normal gene enter the bone marrow, they reproduce quickly and replace stem cells that have the abnormal gene. So, ultimately, the patient with SCID produces B and T cells normally and can fight off infections without antibiotics or other treatment. The long-term effects of gene therapy are unknown, since the children treated are still very young.

Prognosis

When SCID is diagnosed early, successful bone marrow transplantation usually corrects the problem and the child lives a normal life. This means children can go to school, mix with playmates, and take part in sports. However, the quality of life for individuals with severe cases of SCID can be greatly impaired if they do not receive a bone marrow transplant. Children with SCID may not live long if they do not receive the proper treatment or if their disease goes undiagnosed.

Resources

PERIODICALS

Buckley, Rebecca H. "Gene Therapy for Human SCID: Dreams Become Reality." Nature Medicine 6 (June 2000): 623.

Stephenson, Joan. "Gene Therapy Trials Show Efficacy." Journal of the American Medical Association 283 (February 2, 2000): 589.

ORGANIZATIONS

Immune Deficiency Foundation. 40 W. Chesapeake Ave., Suite 308, Towson, MD 21204. (800) 296-4433. Fax: (410) 321-9165. <http://www.primaryimmune.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

International Patient Organization for Patients with Primary Immunodeficiencies. <www.ipopi.org>.

Pediatric Primary ImmuneDeficiency. <www.pedpid.com>.

Severed Combined ImmuneDeficiency Homepage. <www.scid.net>.

Catherine L. Tesla, MS, CGC

Severe combined immunodeficiency

Definition

SCID, or severe combined immunodeficiency, is a group of rare, life-threatening diseases present at birth that impair the immune system. Without a healthy immune system the body cannot fight infections and individuals can easily become seriously ill from common infections.

Description

SCID is one type of Primary Immunodeficiency Diseases (PID) and is considered the most severe. There are approximately 70 forms of PID. Primary immunodeficiency diseases are where a person is missing a component of the immune system—either an organ or cells of the immune sytem. Some deficiencies are deadly, while others are mild.

SCID is also known as the "boy in the bubble" syndrome, because living in a normal enviroment can be fatal. SCID initially was called Swiss agammaglobulinemia because it was first described in Switzerland in 1961. Any exposure to germs can pose a risk for infection, including bacterial, viral, and fungal. In the first few months of life, children with SCID become very ill with infections such as pneumonia (infection of the lungs which prevents oxygen from reaching the blood, making breathing difficult), meningitis (infection of the covering of the brain and spinal cord), sepsis (infection in the bloodstream) and chickenpox, and can die within the first year of life, since their immune system is unable to fight off these infections.

Children with SCID do not respond to medications like other children because their immune system does not function properly. They may also not have a developed thymus gland. Medication usually stimulates a person's immune system to fight infection, but in the case of SCID, the immune system is unable to respond. The immune system is a complex network of cells and organs that protect the body from infection. The thymus and lymphatic system (lymph nodes and lymphatic vessels) house and tranport two very important cells that fight infection: the B and T cells. The bone marrow (center of bones) produces cells that become blood cells as well as cells for the immune system. One type of cell, called lymphocytes or white blood cells, mature in the bone marrow to form "B" cells, while others mature in the thymus to become "T" cells. B and T cells are the two major groups of lymphocytes that recognize and attack infections. Children with SCID have either abnormal or absent B and T cells.

Other infections can be seen in children with SCID including skin infections, yeast infections in the mouth and diaper area, diarrhea, and infection of the liver. Children with SCID fail to gain weight and grow normally. Treatment for SCID is available, however, many children with SCID are not diagnosed in time and die before their first birthday.

A diagnosis of SCID, besides being painful, frightening, and frustrating, needs to be made quickly since common infections can prove fatal. In addition, permanent damage can result in the ears, lungs, and other organs.

Genetic profile

SCID is a group of inherited disorders with about half inherited by a gene on the X chromosome called IL2RG, 15% inherited by an autosomal recessive gene called ADA, and the remaining 35% caused by either an unknown autosomal recessive gene or are the result of a new mutation.

Genetic information is carried in tiny packages called chromosomes . Each chromosome contains thousands of genes and each gene contains the information for a specific trait. All human cells (except egg and sperm cells) contain 23 pairs of chromosomes for a total of 46 chromosomes. One of each pair of chromosomes is inherited from the mother and the other is inherited from the father. SCID is usually inherited in one of two ways: X-linked recessive or autosomal recessive. Autosomal recessive means that the gene for the disease or trait is located on one of the first 22 pairs of chromosomes, which are also called autosomes. Males and females are equally likely to have an autosomal recessive disease or trait. Recessive means that two copies of the gene are necessary to express the condition. Therefore, a child inherits one copy of the gene from each parent, who are called carriers (because they have only one copy of the gene). Since carriers do not express the gene, parents usually do not know they carry the SCID gene until they have an affected child. Carrier parents have a 1-in-4 chance (or 25%) with each pregnancy, to have a child with SCID.

The last pair of human chromosomes, either two X's (female) or one X and one Y (male)—determines gender. X-linked means the gene causing the disease or trait is located on the X chromosome. The term "recessive" usually infers that two copies of a gene—one on each of the chromosome pair—are necessary to cause a disease or express a particular trait. X-linked recessive diseases are most often seen in males, however, because they only have one copy of the X chromosome. Therefore, if a male inherits a particular gene on the X chromosome, he expresses the gene, even though he only has a single copy. Females, on the other hand, have two X chromosomes, and therefore can carry a gene on one of their X chromosomes yet not express any symptoms. (Their second X chromosome copy works normally). A mother usually carries the gene for SCID unknowingly, and has a 50/50 chance with each pregnancy to transmit the gene. If the child is a male, he will have SCID; if the child is female, she will be a carrier for SCID like the mother.

New mutations—alterations in the DNA of the gene—can cause disease. In these cases, neither parent has the disease-causing mutation. This may occur because the mutation in the gene happened for the first time only in the egg or sperm for that particular pregnancy. New mutations are thought to happen by chance and are therefore referred to as "sporadic", meaning, by chance.

Demographics

It is estimated that about 400 children a year are born with some type of primary immunodeficiency disease. Approximately one in 100,000 children are born with SCID each year, regardless of the part of the world the child is from, or the ethnic background of the parents. This disease can affect both males and females depending on its mode of inheritance .

Signs and symptoms

Babies with SCID fail to thrive, are frail, and do not grow well. They have numerous, serious, life-threatening infections that usually begin in the first few months of life. Because they do not respond to medications like other children, they may be on antibiotics for 1-2 months with no improvement before a physician considers a diagnosis of SCID. The types of infections typically include chronic (developing slowly and persisting for a long period of time) skin infections, yeast infections in the mouth and diaper area, diarrhea, infection of the liver, pneumonia, meningitis, and sepsis. They can also have serious sinus and ear infections, as well as a swollen abdomen. Sometimes deep abscesses occur, which are pockets of pus that form around infections in the skin or in the body organs.

Diagnosis

About half of children who see a doctor for frequent infections are normal; another 30% may have allergies, 10% have some other type of serious disorder, and 10% have a primary or secondary immunodeficiency. A diagnosis of SCID is usually made based on a complete medical history and physical examination, in addition to multiple blood tests and chest x rays. The gene in X-linked recessive SCID is called the interleukin receptor gamma chain gene or IL2RG. The autosomal recessive forms of SCID are caused by a variety of different genes; one of the more common is called the adenosine deaminase gene or ADA. Since newborns do not routinely have a test to count white blood cells, SCID is not usually suspected and then diagnosed until the child develops their first infection. A pattern of recurrent infections suggests an immunodeficiency.

Once a couple has had a child with SCID, and they have had the genetic cause identified by DNA studies (performed from a small blood sample), prenatal testing for future pregnancies may be considered on a research basis for some types of SCID. (Note that prenatal testing may not be possible if a mutation cannot be identified). Prenatal diagnosis is available via either CVS (chorionic villus sampling) or amniocentesis . CVS is a biopsy of the placenta performed in the first trimester or the first 12 weeks of pregnancy under ultrasound guidance. Ultrasound is the use of sound waves to visualize the locations of the developing baby and the placenta. The genetic makeup of the placenta is identical to the fetus (developing baby) and therefore the prescence or absence of one of the SCID genes can be determined from this tissue. Amniocentesis is a procedure performed under ultrasound guidance where a long thin needle is inserted into the mother's abdomen, into the uterus, to withdraw a couple of tablespoons of amniotic fluid (fluid surrounding the developing baby) to study. The SCID gene can be studied using cells from the amniotic fluid. Other genetic tests, such as a chromosome analysis, may also be performed on either a CVS or amniocentesis. A small risk of miscarriage is associated with CVS and amniocentesis.

Treatment and management

The best treatment for SCID is a bone marrow transplant (BMT). A bone marrow transplant involves taking cells that are normally present in bone marrow (the center of bones that produce and store blood cells), and giving them back to the child with SCID or to another person. The goal of BMT is to infuse healthy bone marrow cells into a person after their own unhealthy bone marrow has been eliminated. BMT helps to strengthen a child with SCID's immune system.

Other treatment for SCID includes treating each infection promptly and accurately. Injections are also available to help boost a child's immune system.

In the year 2000, gene therapy was first reported to be successful in two French patients with SCID. The idea behind gene therapy is to replace an abnormal gene with a normal copy. In SCID, bone marrow is removed to isolate the patients' stem cells. Stem cells are special cells in the bone marrow that produce lymphocytes. In a laboratory, the normal gene is added to the abnormal stem cells. The genetically altered stem cells now have the normal gene and are transplanted back into the patient. Once the functioning stem cells with the normal gene enter the bone marrow, they reproduce quickly and replace stem cells that have the abnormal gene. So, ultimately, the patient with SCID produces B and T cells normally and can fight off infections without antibiotics or other treatment. The long-term effects of gene therapy are unknown, since the children treated are still very young.

Prognosis

When SCID is diagnosed early, successful bone marrow transplantation usually corrects the problem and the child lives a normal life. This means children can go to school, mix with playmates, and take part in sports. However, the quality of life for individuals with severe cases of SCID can be greatly impaired if they do not receive a bone marrow transplant. Children with SCID may not live long if they do not receive the proper treatment or if their disease goes undiagnosed.

Resources

PERIODICALS

Buckley, Rebecca H. "Gene Therapy for Human SCID: Dreams Become Reality." Nature Medicine 6 (June 2000): 623.

Stephenson, Joan. "Gene Therapy Trials Show Efficacy." Journal of the American Medical Association 283 (February 2, 2000): 589.

ORGANIZATIONS

Immune Deficiency Foundation. 40 W. Chesapeake Ave., Suite 308, Towson, MD 21204. (800) 296-4433. Fax: (410) 321-9165. <http://www.primaryimmune.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

International Patient Organization for Patients with PrimaryImmunodeficiencies.<www.ipopi.org>.

Pediatric Primary ImmuneDeficiency.<www.pedpid.com>.

Severed Combined ImmuneDeficiency Homepage. <www.scid.net>.

Catherine L. Tesla, MS, CGC

Severe Combined Immunodeficiency

Definition

Severe combined immunodeficiency (SCID) is the most serious human immunodeficiency disorder(s). It is a group of congenital disorders in which both the humoral part of the patient's immune system and the cells involved in immune responses fail to work properly. Children with SCID are vulnerable to recurrent severe infections, retarded growth, and early death.

Description

SCID is thought to affect between one in every 100,000 persons, and one in every 500,000 infants. Several different immune system disorders are currently grouped under SCID:

• Swiss-type agammaglobulinemia. This was the first type of SCID discovered, in Switzerland in the 1950s.
• Adenosine deaminase deficiency (ADA). About 50% of SCID cases are of this type. ADA deficiency leads to low levels of B and T cells in the child's immune system.
• Autosomal recessive. About 40% of SCID cases are inherited from the parents in an autosomal recessive pattern.
• Bare lymphocyte syndrome. In this form of SCID, the white blood cells (lymphocytes) in the baby's blood are missing certain proteins. Without these proteins, the lymphocytes cannot activate the T cells in the immune system.
• SCID with leukopenia. Children with this form of SCID are lacking a type of white blood cell called a granulocyte.

In order to understand why SCID is considered the most severe immunodeficiency disorder, it is helpful to have an outline of the parts of the human immune system. It has three parts: cellular, humoral, and nonspecific. The cellular and humoral parts of the system are both needed to fight infections-they recognize disease agents and attack them. The cellular system is composed of many classes of T-lymphocytes (white blood cells that detect foreign invaders called antigens). The humoral system is made up of B cells, which are the only cells in the body that make antibodies. In SCID, neither the cellular nor the humoral part of the immune system is working properly.

Causes and symptoms

SCID is an inherited disorder. There are two ways in which a developing fetus' immune system can fail to develop normally. In the first type of genetic problem, both B and T cells are defective. In the second type, only the T cells are abnormal, but their defect affects the functioning of the B cells.

For the first few months of life, a child with SCID is protected by antibodies in the mother's blood. As early as three months of age, however, the SCID child begins to suffer from mouth infections (thrush), chronic diarrhea, otitis media and pulmonary infections, including pneumocystis pneumonia. The child loses weight, becomes very weak, and eventually dies from an opportunistic infection.

Diagnosis

SCID is diagnosed by the typing of T and B cells in the child's blood. B cells can be detected by immunofluorescence tests for surface markers (unique proteins)on the cells. T cells can be identified in tissue sections (samples) using enzyme-labeled antibodies.

Treatment

Patients with SCID can be treated with antibiotics and immune serum to protect them from infections, but these treatments cannot cure the disorder. Bone marrow transplants are currently regarded as one of the few effective standard treatments for SCID.

Investigational treatments

In 1990, the Food and Drug Administration (FDA) approved PEG-ADA, an orphan drug (not available in US but available elsewhere), for the treatment of SCID. PEG-ADA, which is also called pegademase bovine, works by replacing the ADA deficiency in children with this form of SCID. Children who receive weekly injections of PEG-ADA appear to have normal immune functions restored. Another treatment that is still in the experimental stage is gene therapy. In gene therapy, the children receive periodic infusions of their own T cells corrected with a gene for ADA that has been implanted in an activated virus.

Prognosis

Currently, there is no cure for SCID. Most untreated patients die before age two.

Prevention

Genetic counseling is recommended for parents of a child with SCID.

Resources

ORGANIZATIONS

Immune Deficiency Foundation. 25 W. Chesapeake Ave., Suite 206, Towson, MD 21204. (800) 296-4433. 〈http://www.primaryimmune.org〉.

National Organization for Rare Disorders. P.O. Box 8923, New Fairfield, CT 06812-8923. (800) 999-6673. 〈http://www.rarediseases.org〉.

KEY TERMS

Adenosine deaminase (ADA)— An enzyme that is lacking in a specific type of SCID. Children with an ADA deficiency have low levels of both B and T cells.

Antigens— A substance that usually causes the formation of an antibody. A foreign invaders in the body.

Autosomal recessive inheritance— A pattern of inheritance of a recessive gene where, among other things, both parents may not show symptoms.

B cell— A type of lymphocyte or white blood cell that is derived from precursor cells in the bone marrow.

Congenital— Present at the time of birth. Most forms of SCID are hereditary as well as congenital.

Gene therapy— An experimental treatment for SCID that consists of implanting a gene for ADA into an activated virus and merging it with some of the patient's own T cells. The corrected T cells are infused back into the patient every few months.

Humoral— Pertaining to or derived from a body fluid. The humoral part of the immune system includes antibodies and immunoglobulins in blood serum.

Lymphocyte— A type of white blood cell that is important in the formation of antibodies.

Orphan drug— A drug that is known to be useful in treatment but lacks sufficient funding for further research and development.

PEG-ADA— An orphan drug that is useful in treating SCID related to ADA deficiency.

T cells— Lymphocytes that originate in the thymus gland. T cells regulate the immune system's response to infections. The thymus gland is small or underdeveloped in children with SCID.

Thrush— A disease of the mouth caused by a yeast, Candida albicans.

Severe combined immunodeficiency

Definition

Severe combined immunodeficiency (SCID) is the most serious primary or congenital human immunodeficiency disorder. It is a group of congenital (present from birth) disorders in which the immune system does not work properly. Children with SCID are vulnerable to recurrent severe infections, retarded growth, and early death.

Description

The immune system is composed of elements that are needed for the body to fight infections by recognizing disease agents and attacking them. It includes many classes of T-lymphocytes (white blood cells that detect foreign proteins called antigens). It also includes B cells, which are the only cells in the body that make antibodies. Natural killer (NK) cells are cells that destroy infected cells. In children with SCID, the immune system does not function properly because T, B, and NK cells are either absent or defective. When the immune system does not function correctly, the child is left open to repeated severe diseases and infections.

Several different immune system disorders are grouped under SCID. These include the following:

• X-linked: The most common form of SCID accounts for about half of all cases. Because this is an X-linked condition, it occurs only in boys. Children with X-linked SCID have low T-cell and natural killer (NK) cell levels but elevated B-cell levels.
• Adenosine deaminase deficiency (ADA): About 20 percent of SCID cases are of this type. ADA deficiency leads to low levels of B and T cells in the child's immune system.
• Janus Kinase 3 (Jak3) deficiency: This form of SCID accounts for about 6 percent of cases. There are very low levels of T and NK cells, or they are not present at all. There is an elevated level of B cells. In this form of SCID the lymphocyte or white blood evaluation is identical to X-linked SCID but is autosomal recessive and, therefore, occurs in girls and boys.

Demographics

The rate of SCID is not perfectly documented. It is estimated that it occurs in between one in 50,000 and one in 500,000 infants. It is about three times more common in boys than in girls.

Causes and symptoms

SCID is an inherited disorder. In all forms of SCID, B and T cells are non-functioning. They may or may not be present in various forms of SCID, but they are always non-functioning. In some forms of SCID, NK cells are also absent or non-funtioning.

For the first few months after birth, a infant with SCID is often protected by antibodies acquired before birth from the mother's blood. As early as three months of age, however, the SCID child begins to suffer from mouth infections (thrush), chronic diarrhea , otitis media , and pulmonary infections, including pneumocystis pneumonia . The child loses weight, becomes very weak, and if untreated eventually dies from an opportunistic infection.

When to call the doctor

If a child has unusual infections, unusually severe infections, infections with unusual organisms, or unusual complications of usual infections, a doctor should be consulted to evaluate for possible immune deficiency. This is particularly important if there is a family history of immune deficiency.

Diagnosis

The first screening test for SCID is a white blood cell count with a count of the lymphocytes (differential) because in most forms of SCID the lymphocyte count will be very low. Blood tests can then be done to test for the numbers of B, T, and NK type lymphocytes. If the numbers of all of these cell types are normal and SCID is still suspected, more specialized tests can be done to test the lymphocyte cell functions. Rarely there are children with SCID who have normal lymphocyte numbers and nonfunctioning cells.

Treatment

Patients with SCID should be treated aggressively with antibiotics for any infection, and intravenous immunoglobulin should be given to replace the antibiotics the children cannot make, but these treatments cannot cure the disorder. Bone marrow transplants are as of 2004 regarded as one of the few effective standard treatments for most types of SCID. For those children with ADA deficiency, ADA infusions are the accepted treatment of choice. Up to 95 percent of children who are treated with bone marrow transplants, especially those who are treated before three months of age, survive.

Investigational treatments

As an example of gene therapy for SCID children with ADA deficiency, the child receives periodic infusions of his or her own T cells corrected with a gene for ADA that has been implanted in an activated virus. This should allow these cells to function normally. Other types of SCID have been treated with gene therapy, but these procedures have been put on hold due to serious complications (malignancies). Researchers are as of 2004 also investigating treating SCID in the yet unborn fetus, which has been done successfully a few times.

Prognosis

There is no cure for SCID. Nearly all untreated patients die before age two, most before one year of age. Children who are treated with bone marrow transplants have a much better prognosis.

Prevention

There is no known way to prevent SCID. Genetic counseling is recommended for parents of a child with SCID who are considering having more children and for potential parents who have a family history of the disease and believe they may be carriers.

Parental concerns

Without prompt treatment SCID is nearly always fatal. Treatment can be very successful if done early, preferably within the first three months of life. Research is continuing into in utero treatment options, and some in utero treatments have been successfully carried out, so fetal screening may be helpful if there is a possibility that the child has SCID.

KEY TERMS

Adenosine deaminase (ADA) —An enzyme that is lacking in a specific type of severe combined immunodeficiency disease (SCID). Children with an ADA deficiency have low levels of both B and T cells.

Antigen —A substance (usually a protein) identified as foreign by the body's immune system, triggering the release of antibodies as part of the body's immune response.

Bcell —A type of white blood cell derived from bone marrow. B cells are sometimes called B lymphocytes. They secrete antibodies and have a number of other complex functions within the human immune system.

Congenital —Present at birth.

Gene therapy —An experimental treatment for certain genetic disorders in which a abnormal gene is replaced with the normal copy. Also called somatic-cell gene therapy.

Lymphocyte —A type of white blood cell that participates in the immune response. The two main groups are the B cells that have antibody molecules on their surface and T cells that destroy antigens.

T cell —A type of white blood cell that is produced in the bone marrow and matured in the thymus gland. It helps to regulate the immune system's response to infections or malignancy.

Thrush —An infection of the mouth, caused by the yeast Candida albicans and characterized by a whitish growth and ulcers.

Resources

BOOKS

Parker, James N., and Philip M. Parker. The Official Parent's Sourcebook on Primary Immunodeficiency. Red Hill, Australia: Icon Health, 2002.

ORGANIZATIONS

Immune Deficiency Foundation. 40 W. Chesapeake Avenue Suite 308, Towson, MD 21204. Web site: <www.primaryimmune.org>.

International Patient Organization for Patients with Primary Immunodeficiencies. Alliance House, 12 Caxton Street, London SW1H 0QS. Web site: <www.ipopi.org>

WEB SITES

Ballard, Barb. The SCID Homepage, September 2004. Available online at <www.scid.net/> (accessed November 14, 2004).

Tish Davidson, A.M. Rebecca J. Frey, PhD

Severe combined immunodeficiency (SCID)

Severe combined immunodeficiency (SCID) is a rare genetic disease that is actually a group of inherited disorders characterized by a lack of immune response, usually occurring in infants less than six months old. SCID is the result of a combination of defects of both T-lymphocytes and B-lymphocytes. Lymphocytes are white blood cells that are made in bone marrow, and many move to the thymus gland where they become specialized immune T and B cells . In healthy individuals, T cells attack antigens while B cells make plasma cells that produce antibodies (immunoglobulins ). However, this immune response in SCID patients is absent making them very susceptible to invading diseases, and thus children with untreated SCID rarely live to the age of two years.

SCID is characterized by three main features. The helper T-lymphocytes are functioning poorly or are absent, the thymus gland may be small and functioning poorly or is absent, and the stem cells in bone marrow, from which mature T- and B-lymphocytes arise, are absent or defective in their function. In all of these situations, little or no antibodies are produced. If, for example, T-lymphocytes are never fully developed, then the immune system can never function normally. Moreover, the results of these defects include the following: impairment of normal functioning T- and B-lymphocytes, negative effects on the maturation process for T-helper and T-suppressor cells, and elimination and damage of the original source of the lymphocytes.

The immune disorders characterized in SCID arise because of the inheritance of abnormal genes from one or both parents. The most common form of SCID is linked to the X chromosome inherited from the mother; this makes SCID more common among males. The second most common defect is caused by the inheritance of both parents' abnormally inactive genes governing the production of a particular enzyme that is needed for the development of immunity , called adenosine deaminase (ADA). Although many defective genes for other forms of SCID have been identified in the last few years, scientists do not fully understand all of the forms of the disease.

There are many specific clinical signs that are associated with SCID. After birth, an infant with SCID is initially protected by the temporarily active maternal immune cells; however, as the child ages, his or her immune system fails to take over as the maternal cells become inactive. Pulmonary problems such as pneumonia , non-productive coughs, inflammation around the bronchial tubes, and low alveolar oxygen levels can affect the diseased infant repetitively. Chronic diarrhea is not uncommon, and can lead to severe weight loss, malnutrition, and other gastrointestinal problem. Infants with the disease have an unusual number of bacterial, fungal, viral, or protozoal infections that are much more resistant to treatment than in healthy children. Mouth thrush and yeast infections, both fungal, appear in SCID patients and are very resistant to treatment. Additionally, chronic bacterial and fungal skin infections and several abnormalities of the blood cells can persist.

Severe combined immunodeficiency is a disease that can be successfully treated if it is identified early. The most effective treatment has been hematopoietic stem cell transplants that are best done with the bone marrow of a sister or brother; however, the parent's marrow is acceptable if the infant is less than three months old. Early treatment can also help to avoid pre-transplant chemotherapy often necessary to prevent rejection of the marrow in older children. This is especially advantageous because chemotherapy can leave the patient even more susceptible to invading bodies. When successful, treatment for SCID corrects the patient's immune system defect, and as of 2002 success rates have been shown to be nearly 80% for the bone marrow transplant.

Gene therapy is the subject of ongoing research, and shows promise as a treatment for SCID. Researchers remove T cells of SCID patients and expose those cells to the ADA gene for ten days, and then return the cells intravenously. Although it was successful in one case, this treatment of SCID is still very much in the experimental stage. Nevertheless, these and other treatments hold potential for the development of a cure for SCID.

See also Immune system; Immunochemistry; Immunodeficiency disease syndromes; Immunodeficiency diseases; Immunogenetics; Immunoglobulins and immunoglobulin deficiency syndromes; Immunological analysis techniques; Immunology