Severe Combined Immunodeficiency (SCID)

Severe combined immunodeficiency or SCID is an inherited genetic disorder affecting the immune system's ability to ward off infections. Different types of SCID have different causative genes, symptoms, and treatments.

Types

SCID is caused by mutations in genes that are needed for the immune system, there are at least ten known types of SCID.^[1] These are grouped by the way in which they are inherited — X-linked or autosomal.

• Autosomal recessive inheritance
  • Autosomal recessive forms of SCID result when a child inherits two defective copies of the same autosomal gene. The parents in this case each carry one normal copy of the gene and one abnormal copy. In the case of an affected child, the child inherits both abnormal copies. One form of SCID is ADA deficiency. This condition results from the lack of an enzyme (specifically, adenosine deaminase) that helps cells to get rid of toxic byproducts. Without ADA, poisons build up and kill the lymphocytes. It was in 1972 that the ADA deficiency form of SCID was recognized,^[2] but ADA deficiency has an autosomal recessive inheritance pattern that affects males and females equally. It was known though that a predominance of SCID patients were male, leading researchers to suspect that an X-linked inheritance also existed.

• X-linked inheritance or X-SCID
  • A female can be a silent carrier of a defective X- chromosome, because her 2nd X chromosome compensates and consequently she is unaffected. A male who inherits the defective X chromosome, however, will be affected. X-linked SCID affects only males and accounts for approximately 45% of all cases of SCID. It wasn't until 1993 that Dr. Jennifer Puck^[3] and Dr. Warren Leonard^[4] simultaneously, but independently, discovered the genetic defect involved in X-linked SCID.

Video of baby with SCID

Colton was born in Feb. 2007 with SCID also known as bubble boy disease. He was diagnosed in December after countless trips to the ER. Colton's immune system does not function the way it should and as a result, he cannot fight infection. Any infection can be fatal. He spent over three months in the hospital including his first Christmas and birthday. This is video from the hospital.

Signs and Symptoms

The primary immunodeficiency diseases, of which SCID is one, were originally viewed as rare disorders, characterized by severe clinical expression early in life. However, it has become clear that these diseases are not as uncommon as originally suspected, that their clinical expression can sometimes be relatively mild, and that they are seen nearly as often in adolescents and adults as they are in infants and children. In fact, immunodeficiency may present so subtly that the diagnosis will be made only if the physician is alert to that possibility. Early diagnosis of immunodeficiency is important so that appropriate therapy can be instituted before there has been end-organ damage. Furthermore, because some primary immunodeficiency diseases are inheritable, early diagnosis is essential for making genetic information available to the families of affected individuals.

Patients with SCID most often are recognized because of their increased susceptibility to infection, but these patients may also have a variety of symptoms.

Chronic diarrhea, ear infections, recurrent pneumonia, and profuse oral candidiasis commonly occur. SCID is the most severe of the primary immune deficiency diseases. The defining characteristic of SCID is the absence of T cells and, as a result, lack of B cell function as well. Unless these defects are corrected the child will die of opportunistic infections before their first or second birthday.

Causes

Diagnosis

X-SCID, like other forms of inherited SCID is most often diagnosed by only after the infant has had serious infections.^[5] Several groups are working to institute newborn screening tests to detect SCID before severe infections occur. Since, effective treatment with stem cell transplantation is widely established, the best outcome for SCID is achieved if hematopoietic stem cell transplantation is performed in the first months of life. The current basis for the screening test is measurement of the number of lymphocytes at the time of birth. In normal infants, lymphocyte numbers are very high, but in SCID infants the numbers are very low. Gene-based screening tests are also being developed. ^[6]

Treatment

Preventing infections

For children with SCID, the first concern is to prevent infections. Children with SCID need to be protected from invading bacteria, viruses and other pathogens. This includes keeping them away from crowds and sick people. Bacterial infections are often treated with antibiotics to prevent infection.

They will also be given intravenous immune globulin (IVIG). Immune globulin is also called immunoglobulin or gammaglobulin. It contains antibodies that would normally be made by the body fight infection. Immune globulin is usually infused into a vein. Patients with SCID will probably get one IVIG infusion a month. Each infusion may take from one to five hours. Treatments may be given in a doctor's office, hospital outpatient unit or at home. Many people have no side effects from IVIG infusion, but some people may have side effects such as chills, headaches, fever, nausea and chest tightness. These can usually be controlled with medicine or adjustments to the rate of infusion.

For one type of SCID, ADA deficiency, the standard treatment is treatment with a form of the ADA enzyme called PEG-ADA.^[7] Treatment with PEG-ADA is effective in about 90% of children. However, some also still need IVIG treatments.

Gene therapy

A treatment option being studied in clinical trials is gene therapy.^[8] Gene therapy has been a successful treatment for some patients with ADA deficiency SCID. At first, gene therapy also appeared to be a promising treatment for X-linked SCID, but some children treated with gene therapy developed leukemia. New trials of gene therapy are in progress.

Transplant

The only known cure for SCID is a bone marrow or cord blood transplant (also called a BMT), in which blood-forming cells from a family member or unrelated donor or cord blood unit are given in the hope that they will develop into a functional immune system in the recipient. The cells of interest are known as stem cells or hematopoietic stem cells.^[9]

The donor must closely match the patient's tissue type. The best donor is usually a matched sibling. Each sibling has a 25% chance of being a suitable match, but since SCID is inherited, many children with SCID do not have a healthy matched sibling. Doctors may also use one of the child's parents or another partly matched family member as a donor.

Unlike transplants for most other diseases, a transplant for SCID may not include a preparative regimen of high-dose chemotherapy. The preparative regimen destroys cells in the bone marrow to make room for the donated cells. It also destroys immune cells so they cannot attack the donated cells. Some children with SCID do not need a preparative regimen because they have so few immune cells.

Patient, disease and transplant factors can affect a child's chances of survival and his or her quality of life after transplant. In general, a child has a higher likelihood for a good outcome when:

• A transplant is done early, within the first few months of life, if possible.
• The child has not had severe infections or shown a failure to thrive.
• The child has a type of SCID with normal B cell function.
• The donor is a close match. A matched sibling offers the highest likelihood of success, but a partly matched (haploidentical) family member or an unrelated donor or cord blood unit can also provide a good outcome.

Whether or not a preparative regimen is used can affect some of the risks of a transplant. Without a preparative regimen, a child avoids risks of serious side effects from the high-dose chemotherapy. However, other risks are increased. The risk that the transplant will not engraft (make new blood cells for the body) is slightly higher. The risk that the child will not develop the B cell function needed for a normal immune system may also be higher. A child who does not develop normal B cell function will need ongoing treatment with IVIG to help his or her immune system fight infection.

Whether a child with SCID receives a preparative regimen may depend on the form of SCID, the donor used and the transplant center. A preparative regimen is used for most transplants from unrelated donors, but is often omitted for transplants from related donors. If you are planning a transplant for your child, you can ask your child's doctor about whether a preparative regimen will be used.

Whether or not the donor's cells are filtered to remove T cells (T-cell depleted) can also affect the outcome. T cells play an important role in the immune system, but they are also involved in a transplant complication called graft-versus-host disease (GVHD). GVHD can range from mild to life-threatening. Whether or not the transplant is T-cell depleted depends on the donor used and the transplant center.

Prognosis

Transplants done before birth and in the first three months of life have a high success rate. If left untreated SCID is usually fatal early in life.

References

1. ↑ Stiehm ER. New and old immunodeficiencies. Pediatr Res. 1993 Jan;33(1 Suppl):S2-7 Abstract
2. ↑ Dissing J, Knudsen B. Adenosine-deaminase deficiency and combined immunodeficiency syndrome. Lancet. 1972 Dec 16;2(7790):1316. Citation
3. ↑ Puck JM, Deschênes SM, Porter JC, et al.The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet. 1993 Aug;2(8):1099-104. Abstract
4. ↑ Noguchi M, Yi H, Rosenblatt HM, et al. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147-57. [1]
5. ↑ Gennery AR, Cant AJ. Diagnosis of severe combined immunodeficiency. J Clin Pathol. 2001 Mar;54(3):191-5. Abstract | PDF
6. ↑ Puck JM et al. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J Allergy Clin Immunol. 2007 Oct;120(4):760-8. Abstract]
7. ↑ Booth C, Hershfield M, Notarangelo L, et al. Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006). Clin Immunol. 2007 May;123(2):139-47. Abstract
8. ↑ Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. 2007 Jun;117(6):1456-65. Abstract | Full Text | PDF
9. ↑ Porta F, Forino C, De Martiis D, et al. Stem cell transplantation for primary immunodeficiencies. Bone Marrow Transplant. 2008 Jun;41 Suppl 2:S83-6. Abstract

External Links

• Genetics Home Reference
• X-linked severe combined immunodeficiency. Diagnosis in males with sporadic severe combined immunodeficiency and clarification of clinical findings. J Clin Invest. 1990 May; 85(5): 1548–1554.
• NHGRI Division of Intramural Research
• SCID.net
• National primary Immunodeficiency Resource Center