Severe combined immunodeficiency syndrome and genetics

ALSO KNOWN AS: SCID; boy in the bubble syndrome; XSCID; SCIDX1; Athabascan SCID; Swiss agammaglobulinemia

DEFINITIONSevere combined immunodeficiency syndrome (SCID) is a group of rare (1 in 100,000), congenital conditions defined by a deficiency of the immune response. A mutation in one of several possible genes causes a defect in the specialized white blood cells (lymphocytes) that defend against infection. Patients are prone to repeated and persistent infections, rarely surviving past their first year unless treated within the first three to four months of life with bone marrow transplantation.

Risk Factors

All forms of SCID, of which there are about twenty, are inherited. The most common form of SCID (approximately half of reported cases) occurs only in males, as it is caused by mutations in the X chromosome (XSCID).

Though the Artemis form of SCID is very rare in the general population, it has a high incidence (1 in 2,000) in Navajo and Apache Native Americans. This form of SCID is also known as Athabascan SCID (SCIDA), after the Athabascan linguistic group of American Indians.

Etiology and Genetics

The immune system is a network of organs, tissues, cells, and protein substances that work together, defending the body against attack by bacteria, viruses, fungi, parasites, or other foreign substances. When a major component of the immune system is not functioning correctly, the body cannot ward off infections. Lymphocytes (T, B, and NK cells) and the proteins they produce make up key components of the immune system. T cells are crucial in identifying invading agents and in activating and regulating other cells of the immune system. The defining characteristic for SCID is a severe defect in T-cell production and function. The different genetic forms of SCID vary as to the presence of defects in NK and B cells.

SCID results from mutations in any one of twelve known genes encoding components involved in lymphocyte development. Since these twelve genetic causes of SCID account for approximately 90 percent of cases, there are probably additional genetic forms of SCID. Note that reticular dysgenesis and Omenn syndrome are sometimes included as SCID disorders (both are characterized by T-cell deficiency); however, the World Health Organization considers these disorders distinct from SCID.

XSCID results from mutations in the interleukin-2 receptor gamma gene (IL2RG; cytogenetic location: Xq13.1). Defective IL prevent the normal development of T cells. SCID also results from autosomal recessive gene defects. Mutations found on autosomal chromosomes have been identified in eleven other genetic forms of SCID with deficiencies in adenosine deaminase (ADA; cytogenetic location: 20q12-q13.11); Janus 3 (JAK3; cytogenetic location: 19p13.1); IL-7 receptor alpha chain (IL-7Rα: cytogenetic location: 5p13); recombinase-activating gene (RAG-1 or RAG-2; cytogenetic location: 11p13); Artemis (cytogenetic location: 10p13); ligase 4 (LIG4; cytogenetic location: 13q33-q34); CD3 delta, epsilon, and zeta chain (CD3δ, CD3ϵ, and CD3ξ; cytogenetic locations: 11q23, 11q23, and 1q22-q23); and CD45 (cytogenetic location: 1q31-q32). These various components of the immune system are critical in T, B, and/or NK cell development or function via their role in toxic byproduct disposal, DNA repair, signal transduction, or VDJ (a form of genetic recombination which assembles pieces of genes encoding specific proteins that have key roles in the immune system).

ADA deficiency is the second most common form of SCID, accounting for about one-sixth of reported cases. Mutations in the ADA gene lead to a deficiency in the and accumulation of toxic byproducts. Though ADA is present in all cell types, immature in the thymus normally have the highest level of ADA in the body and are thus particularly sensitive to the toxic effects of these by-products. Without ADA, immature lymphocytes fail to reach maturity and die.

Symptoms

Young children often catch colds. However, a baby with SCID develops more serious and life-threatening infections. Bacteria or viruses that typically cause little to no illness in normal children may cause serious illness in SCID children. For example, Pneumocystis jiroveci and Cytomegalovirus, both of which are found in healthy people, can cause a fatal pneumonia or hepatitis in SCID children. Similarly, usually produces a sore throat and cold in people in the general population but can cause a fatal hepatitis in SCID children. SCID children may also develop severe fungal infections such as thrush (a Candida fungal infection of the mouth). Additionally, they are at risk from the live viruses used in certain vaccines. Other symptoms include persistent diarrhea (not necessarily infection-related), rash, and autoimmunity.

Screening and Diagnosis

Though SCID is considered rare, some experts believe it may be more common than thought. Children may be dying of SCID infections before being diagnosed. For example, some cases of sudden infant death syndrome (SIDS) may actually be due to SCID. Nonetheless, standard screening of newborns to diagnose SCID before infections occur is generally not done because the disease is rare and has a diverse genetic etiology and testing is expensive. Testing for SCID is performed if there is a known family history of the disease or the baby exhibits suggestive symptoms (such as persistent and recurrent infections). Wisconsin was the first state to screen newborns for SCID in 2008, and by 2018, all fifty US states, the District of Columbia, and two US territories screened for the condition.

Current screening methods include measurement of lymphocyte counts (very low in SCID) and population-based screening using IL-7 or TREC. Ongoing studies are evaluating new methods for their value in screening newborns for the early diagnosis of SCID. Most promising is the DNA gene chip that can detect the expression of thousands of genes simultaneously and may be able to detect both known and new mutations.

If SCID is suspected, the following tests may aid diagnosis: complete blood counts (low lymphocyte counts in SCID); T, B, and NK cell counts (T cells are absent or dysfunctional in all forms of SCID; NK and may be absent depending on the form of SCID); and levels (low in SCID; may be artificially high during the first three to four months of life due to maternal antibodies that cross the placenta during pregnancy). Specific genetic testing to identify underlying genetic defects is possible in about 90 percent of cases.

Treatment and Therapy

Initially, infections are treated with antibiotics, antifungal and antiviral drugs, and intravenous immunoglobulin (IVIg). However, the restoration of a functional immune system is necessary. The preferred treatment is bone marrow transplantation from a healthy donor. If performed within the first three to four months of life, it is effective in the majority of patients. Blood-forming stem cells from the bone marrow of a healthy donor provide a functioning immune system that can protect the patient against infection. These stem cells can renew themselves as needed and produce a continuous supply of healthy immune cells.

In the ADA deficiency form of SCID, enzyme replacement therapy with weekly injections of polyethylene glycol-modified bovine ADA allows the immune cells to recover. This treatment is effective in the majority of cases.

Gene therapy is still a considered an experimental treatment option for SCID, and studies are ongoing. In this treatment, researchers correct the DNA mutation in a sample of the patient’s T cells and then return these corrected T cells to the patient. Though this therapy has been successful in some patients, serious complications, such as a leukemia-like disorder, have occurred in others.

According to the US National Institutes of Health, all children with confirmed SCID from 2010 to 2018 received a transplant of blood-forming stem cells. Infants who received a transplant from a genetically matched sibling had a very high five-year survival rate. Among those who received a transplant from an unknown genetic match, the five-year survival rate was 87 percent among all children and 92.5 percent among those whose condition was detected by a screening.

Prevention and Outcomes

Genetic counseling is recommended if there is a family history of the disease. Early diagnosis allows for early treatment and would significantly improve chances of a good outcome.

Bibliography

"About Severe Combined Immunodeficiency." National Human Genome Research Institute, 2 June 2014, www.genome.gov/Genetic-Disorders/Severe-Combined-Immunodeficiency. Accessed 9 Sept. 2024.

Immune Deficiency Foundation. IDF Patient and Family Handbook: For Primary Immunodeficiency Diseases. 5th ed. Towson: Author, 2013. Print.

“Newborn Screening for Severe Combined Immunodeficiency (SCID): A Review.” Frontiers in Bioscience 10 (2005): 1024–39. Print.

"Severe Combined Immunodeficiency (SCID)." National Bone Marrow Donor Program, 2024, www.nmdp.org/patients/understanding-transplant/diseases-treated-by-transplant/severe-combined-immunodeficiency. Accessed 9 Sept. 2024.

"Screening Newborns for Deadly Immune Disorder Saves Lives." National Institutes of Health, 11 July 2023, www.nih.gov/news-events/nih-research-matters/screening-newborns-deadly-immune-disorder-saves-lives. Accessed 9 Sept. 2024.

"Test Reliably Detects Inherited Immune Deficiency in Newborns." National Institutes of Health, 20 Aug. 2014, www.nih.gov/news-events/news-releases/test-reliably-detects-inherited-immune-deficiency-newborns. Accessed 9 Sept. 2024.