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Severe Combined Immunodeficiency

Synonyms of Severe Combined Immunodeficiency

  • Bubble Boy Syndrome
  • SCID

Disorder Subdivisions

  • ADA Deficiency
  • Adenosine Deaminase Deficiency
  • Autosomal Recessive Severe Combined Immunodeficiency
  • Bare Lymphocyte Syndrome
  • Reticular Dysgenesis
  • X-Linked Recessive Severe Combined Immunodeficiency with Leukopenia

General Discussion

Severe Combined Immunodeficiency (SCID) is a group of rare congenital syndromes characterized by little if any immune responses. This results in frequent recurring infections. Cellular immune responses involve specialized white blood cells known as T lymphocytes or "killer cells". These cells assist other white blood cells (B lymphocytes) to respond to infectious, foreign agents that invade the body (i.e., bacteria or viruses). The B lymphocytes maintain immunity by enabling the body to produce and preserve circulating antibodies.

People with Severe Combined Immunodeficiency are unusually susceptible to recurrent infections with bacteria, viruses, fungi, and other infectious agents that can be life-threatening.

There are several types of Severe Combined Immunodeficiencies. These include: Autosomal Recessive Severe Combined Immunodeficiency, X-Linked Recessive Severe Combined Immunodeficiency, Adenosine Deaminase Deficiency (ADA), Bare Lymphocyte Syndrome, Severe Combined Immunodeficiency with Leukopenia (Reticular Dysgenesis), and Swiss-type Agammaglobulinemia. Each type of Severe Combined Immune Deficiency is caused by a different genetic defect, but the primary symptom is reduced or absent immune functions, and all types are hereditary.

Symptoms

Newborns with Severe Combined Immunodeficiency (SCID) acquire antibodies from their mothers which continue to protect them from recurrent infections during the first few months of life. After they lose these antibodies, infections tend to occur and recur frequently. Symptoms may include episodes of diarrhea, pneumonia, infection of the blood stream (sepsis), repeated inflammation of the middle ear (otitis media), and/or skin infections. Weight loss, weakness, and/or growth retardation may also occur.

Organisms that would cause mild to moderate illnesses in healthy individuals may cause life-threatening infections in children with Severe Combined Immunodeficiency. Even organisms that do not ordinarily make people sick may make a child with Severe Combined Immunodeficiency very ill (opportunistic infections). Typical infections may include yeast infections (Candida albicans), reaction to smallpox vaccination (generalized vaccinia), chicken pox (varicella), measles, cytomegalovirus, and live bacteria in certain vaccines. Pneumocystis carinii pneumonia is common in children with SCID and can be very difficult to treat. (For more information on these disorders, choose "Opportunistic Infections," "Candidiasis," "Varicella," "Cytomegalovirus," and "Pneumocystis Pneumonia" as your search terms in the Rare Disease Database.)

Cells able to produce antibodies (immunocompetent) that are given to children with Severe Combined Immunodeficiency (i.e., through blood transfusion) may cause Graft-Versus-Host (GvH) Disease. This disease causes a reaction in the recipient's skin, liver, gastrointestinal system, and/or bone marrow. (For more information on this disorder, choose "Graft-Versus- Host" as your search term in the Rare Disease Database.)

Since transplanted tissues are not rejected by a person with Severe Combined Immunodeficiency, bone marrow transplantation is less difficult than in other people, and in some cases can be an effective treatment for this disorder. If children with SCID are immunized, antibodies are not formed. If immunization is with a live vaccine, life-threatening infections can occur. People with this disorder do not have any reactions on their skin to antigens and do not develop allergic reactions.

People with Severe Combined Immunodeficiency usually have severely reduced levels of T and B lymphocytes in their blood stream. Levels of immunoglobulins in the fluids of the body (serum) are also extremely low or absent. If any immunoglobulins are present, their function is greatly impaired. The thymus, which is the primary gland of the lymphatic system, is typically small and underdeveloped. Lymph nodes usually lack lymphocytes and tonsils, adenoids, and/or other lymphoid organs are poorly developed or absent in children with this disorder.

In Severe Combined Immunodeficiency (SCID) with Leukopenia (reticular dysgenesis), other white blood cells known as granulocytes are also absent or greatly reduced in number. These specialized cells function to engulf invading microorganisms, especially bacteria.

Causes

Some cases of Severe Combined Immunodeficiency (SCID) may be inherited as an autosomal recessive genetic trait. Approximately 50 percent of children with autosomal recessive SCID have a deficiency of the enzyme adenosine deaminase (ADA). This form of the disease is known as SCID-ADA.

Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Approximately 50 percent of the cases Severe Combined Immunodeficiency may be inherited as an X-linked recessive genetic trait. The location of the gene that is responsible for the X-linked recessive form of SCID is located on the long arm of the X chromosome (Xq12-13). A number of different genetic changes (point mutations) have been identified. Some studies in the medical literature suggest that this defect may affect the function and maturation of T cells.

X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons.

The symptoms of severe combined immunodeficiency usually result from one of three factors: absence or improper function of certain white blood cells (helper T-cells), absence or improper function of the thymus gland, or absent or defective bone marrow stem cells (from which helper T cells and B lymphocytes develop).

SCID-ADA are a result of an abnormal deficiency of the enzyme adenosine deaminase. The gene for this enzyme is located on the long arm of chromosome 20 (20q12-13.11).

Researchers at the National Institutes of Health, National Heart, Lung and Blood Institute in Bethesda, MD are studying a defect in the interleukin- 2 receptor gene as a possible cause for X-linked Severe Combined Immunodeficiency. Interleukin-2 is a hormone that helps to regulate the disease fighting abilities of blood cells. It is thought that in X-linked Severe Combined Immunodeficiency, this receptor may not be constructed properly.

In the Bare Lymphocyte Syndrome, the symptoms of Severe Combined Immunodeficiency are associated with impaired function of lymphocytes (lack of compatible antigens and B2 microglobulin), which prevents T cells from activating or maturing.

Affected Populations

All types of Severe Combined Immunodeficiency (SCID) are very rare disorders that occur in approximately 1 in 100,000 to 1 in 500,000 births in the United States. Adenosine Deaminase Deficiency (SCID-ADA) and recessive forms of Severe Combined Immunodeficiency affect males and females in equal numbers. The X-linked form of this disorder affects mostly males although some women may experience mild symptoms of the disorder if they are carriers of the genetic defect. This type of Severe Combined Immunodeficiency occurs in approximately 1 in 100,000 births in the United States.

Related Disorders

Symptoms of the following disorders can be similar to those of Severe Combined Immunodeficiency. Comparisons may be useful for a differential diagnosis:

Primary Agammaglobulinemias (X-linked Immunodeficiency) are a group of inherited immune deficiencies characterized by insufficient antibodies. The most frequent symptoms of these disorders are repeated bacterial infections. Bacterial infections are a frequent cause of chronic inflammation of the intestines and diarrhea. Repeated infections of the middle ear and respiratory tract may also occur. Areas of patchy, reddish skin may appear around the eyes, fingers, knees, and ankles. Some children with Primary Agammaglobulinemias experience joint swelling and pain. This disease is treated with infusions of immune globulins which prevent infections. (For more information on this disorder, choose "Primary Agammaglobulinemias" as your search term in the Rare Disease Database.)

DiGeorge Syndrome is a very rare immune deficiency that results from developmental defects in the thymus and parathyroid glands. This disorder is characterized by seizures during the first few days of life due to the abnormal function of the parathyroid gland. Inability to fight off frequent infections from viruses, fungi, and other bacteria is characteristic of this disorder. Children with DiGeorge Syndrome frequently have chronic nasal infections, diarrhea, oral candidiasis, and Pneumocystis pneumonia. (For more information on this disorder, choose "DiGeorge" as your search term in the Rare Disease Database.)

Wiskott-Aldrich Syndrome is a rare inherited disorder (X-linked) characterized by an immune deficiency primarily affecting B lymphocytes. The symptoms generally begin during infancy and may include excessive bleeding from circumcision or minor trauma, scaly red skin rashes, and abnormally low levels of circulating blood platelets (thrombocytopenia). Individuals with this disorder also have defects in their ability to resist infection and commonly experience infections of the middle ear (otitis media), acute inflammation of the lungs (pneumonia), inflammation of the membranes that cover the brain and spinal cord (meningitis), and systemic bacterial infection in the blood (sepsis). (For more information on this disorder, choose "Wiskott-Aldrich" as your search term in the Rare Disease Database.)

There are various other forms of immunodeficiencies. They include AIDS (Acquired Immune Deficiency Syndrome), isolated defects of T cell function, and various antibody disorders. However, AIDS is not an inherited immune deficiency. Rather, it is caused by a virus. (For more information on this disorder, choose "Acquired Immune Deficiency Syndrome [AIDS]" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
The diagnosis of SCID is suspected based upon identification of characteristic physical findings and a thorough clinical evaluation. The diagnosis of SCID-ADA can be made before birth (in utero) through amniocentesis, a procedure during which a small amount of amniotic fluid, which contains fetal cells, is removed and studied. Deficiency of the enzyme adenosine deaminase can be detected in these cells.

In infants suspected of having SCID a blood smear test may be used to count the number of lymphocytes in the infant's blood. Some affected individuals will display low levels of lymphocytes. However, some individuals with SCID may have normal levels of lymphocytes. In such cases, tests to determine whether lymphocytes are functioning proper may be administered.

Treatment
In some cases bone marrow transplantation can cure Severe Combined Immunodeficiency if an identical donor match can be found to donate the marrow. This procedure has also been tried with bone marrow cells that have one set of identical chromosomes (haplo-identical), usually from a parent. However, bone marrow transplants are high risk procedures. Affected individuals must receive high doses of chemotherapy, followed by radiation therapy. Donor bone marrow cells are then given intravenously to the patient.

In a few isolated cases of Severe Combined Immunodeficiency, agents such as transfer factor, thymosin, or levamisole may boost any existing cellular immunities.

In 1990 the orphan drug PEG-ADA (Adagen) was approved as an enzyme replacement therapy for adenosine deaminase. Some children taking PEG-ADA through a weekly injection have had a near normal immune system restored, and they can now recover from infections that might previously have been life- threatening. For more information on PEG-ADA, the manufacturer is:

Enzon, Inc. 40 Kingsbridge Rd. Piscataway, NJ 08854-3998 (908) 980-4500

Infections in persons with Severe Combined Immunodeficiency must be treated immediately and vigorously with antifungal, antibiotic, and supportive measures. Pneumonia caused by the bacteria Pneumocystis carinii can be extremely difficult to treat. There are several drugs such as trimethoprim-sulfamethoxazole and the orphan drug pentamidine idethionate that are usually used to treat this resistant form of pneumonia.

Cytomegalovirus and generalized herpes simplex infections are typically treated with the drugs idoxuridine, floxuridine, or cytarabadine. Severe candidiasis and other fungal infections usually respond to treatment with the antifungal drug amphotericin B.

The Food and Drug Administration (FDA) recommends that individuals with weakened immune systems such as those with primary immunodeficiency disorders should exercise caution when consuming certain fruit and vegetable juices. The FDA recommends that such individuals should drink only pasteurized versions of these juices, since unpasteurized juices may contain harmful bacteria that could cause overwhelming infectious illnesses.

Genetic counseling will be of benefit for individuals with Severe Combined Immunodeficiency and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

In May, 2010, a new gene therapy trial for SCID-X1 began. The international trial, developed at Children's Hospital Boston, is the first to be approved by the FDA for SCID-X1 since 2005, since five children developed leukemia after being treated in Paris and London Stem cells will be removed from the patient's bone marrow, a normal gene inserted, and then infused back into the patient. The vector for the gene transfer, a retrovirus, has been completely redesigned and the likely cancer-causing elements eliminated. The goals of this therapy are to restore immune function while avoiding the problems that occur with stem cells from parents and unrelated people, such as repeat transplants, incomplete cure of the immune system, exposure to chemotherapy, and graft versus host disease.

For more on the trial, "Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector" (NCT01129544), visit http://clinicaltrials.gov/ct2/show/NCT01129544?term=SCID&rank=2.

For information on enrollment, contact Adam C. Simmons, MPH at Children's Hospital Boston (adam.simmons@childrens.harvard.edu).

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Severe Combined Immunodeficiency Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:

Behrman RE., ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:

Buyse ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; 1990:949-951, 959-961.

JOURNAL ARTICLES
Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002;296:2410-13.

Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002;346:1185-93.

Cavazzana-Calvo M, et al., Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288:669-72.

Bollinger ME, et al., Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency. N Engl J Med. 1996;334:1367-71.

Volker S, et al., Atypical x-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med. 1996; 335:1563-7.

Flaske AW, et al., Treatment of x-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. N Engl J Med. 1996;335:1806-10.

Ochs HD, Antibody responses to bacteriophage phi X174 in patients with adenosine deaminase deficiency. Blood. 1992;80:1163-71.

Noguchi M, Interleukin-2 receptor gamma chain mutation results in x-linked severe combined immunodeficiency in humans. Cell. 1993;73:147-57.

Fischer A, Severe combined immunodeficiencies. Immunodefic Rev. 1992;3:83-100.

Jhanwar SC, et al., Localization of human adenosine deaminase (ADA) gene sequences to the q12-q13.11 region of chromosome 20 buy in situ hybridization. Cytogenet Cell Genet. 1989;50:168-71.

Byuckley RH, Immunodeficiency. R.H. Buckley; J Allergy Clin Immunol. 1983;72:627-41.

Webster AD, Metabolic defects in immunodeficiency diseases. Clin Exp Immunol. 1982;49:1-10.

FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:102700; Last Update:12/17/98. Entry No:202500; Last Update:2/18/99. Entry No:300400; Last Update:5/2/2000.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2010/07/19 00:00:00 GMT+0

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