Severe Combined Immunodeficiency (SCID)

SCID can affect either boys or girls of any race or ethnicity. Defects of at least 20 different genes may result in SCID. Sometimes doctors can determine that a child has SCID but the underlying gene defect cannot be found (despite extensive searches for a gene defect). This is because in some cases, we do not yet know the gene that is responsible for the SCID. The most common form (about 20% of cases) occurs in boys and is inherited as an X-linked disease, meaning that females (mothers) may carry the abnormal gene for the disorder but don’t develop symptoms, whereas male children born to them carry the risk of developing the clinical problems associated with the disease. SCID is estimated to occur in approximately one out of every 58,000 births. (Kwan et al. Newborn screening for severe combined immune deficiency in 11 screening programs in the United States.

The frequency and severity of infections are the most helpful clues that a patient may have a problem with their immune system. For patients with symptoms suggestive of SCID, the following tests can be helpful in making a definitive diagnosis:

• Complete Blood Counts (CBC with differential) –often shows low lymphocyte counts (although in some situations, the total lymphocyte count may be in the normal range, and sometimes, even higher than normal). Patients with SCID are susceptible to infections because they are missing one or more types of lymphocytes.
• T cell, B cell, and NK cell counts –T cells are absent or dysfunctional in all forms of SCID. B cells and NK cells may be absent depending on which type of SCID a patient has.
• Immunoglobulin levels (IgG, IgM, IgA, IgE) – Immunoglobulins (antibodies) are made by the lymphocytes so they are usually low in SCID.
• Specific genetic testing - There are at least 20 known genetic causes of SCID, making it possible to identify an underlying genetic defect in about 90% of cases. Mutations in different genes are accompanied by characteristic immune abnormalities that can assist in making the diagnosis.
• A growing number of states are currently performing newborn screening for SCID with the TREC assay. As of May 2015, about 70% of all newborns in the United States are screened at birth. As this process expands to other states, most children with SCID will be diagnosed very early in life, increasing their chances for successful treatment.

Treatment for SCID may include the following:

• Medications – especially antibiotic, antifungal, and antiviral medications to treat or prevent active infections.
• Avoiding exposure to infections, especially ones that may be difficult to eradicate, such as chicken pox.
• Use immunoglobulin supplementation (IVIg)
• Blood and Marrow Transplantation – BMT provides patients with a functioning immune system that is capable of protecting them from infections. It can be a cure for SCID, and is highly effective in many patients, with best outcomes when an HLA-matched sibling donor is available, and if done early in life.
• Enzyme replacement therapy – For patients with the type of SCID caused by deficiency of the enzyme Adenosine Deaminase (ADA), enzyme replacement therapy (with a medication known as SC-PEG-rADA (elapegademase; Revcovi ®) may be used to enable immune cells to recover. This may allow patients more time to get to transplant with better immunity. In some instances, SC-PEG-rADA may be used for years (without transplant) and be helpful in restoring immunity and preventing infections.
• Gene therapy - Patients with some types of SCID have also undergone gene therapy to correct the genetic mutation in their immune cells. While this has been very successful in some patients there have been some serious complications and, at this point, gene therapy is still considered an investigational treatment option. There are ongoing clinical trials of gene therapy for ADA-SCID and X-SCID in the US and Europe using next generation vectors which appear to be more efficient and safer. There are plans for trials for RAG-SCID and Artemis-SCID in the next few years.

There is increasing recognition that a number of serious immune deficiencies may not meet the laboratory criteria to be called SCID, but the types of infections seen are similar to patients with the more classical forms of SCID. Many of these cases of “leaky” or “atypical” SCID involve similar gene mutations as found in classical SCID.

For instance, person one could have a mutation in a gene called RAG1, resulting in a very low T-cell count, serious infections, and a diagnosis of SCID. Person two could have a different gene mutation in the same gene (RAG1), but person two has a higher T-cell count than person one. This may make doctors unable to diagnose person two as having classic SCID. Nonetheless, person two may still experience severe infections, similar to a patient with classic SCID. In these situations, person two may be diagnosed with leaky SCID.

Patients with leaky SCID may experience severe infections similar to a patient with classical SCID, or they may have less severe or less frequent infections. Some people with Leaky SCID may not be diagnosed until they are older (sometimes after one year of age and even in to the adult years). Sometimes leaky SCID may present less with infections and more often with autoimmune problems. Autoimmune (auto = self; immune = immune system) problems occur when the person’s own immune system attacks the patient. Autoimmune thrombocytopenia (low platelet count resulting in bleeding), autoimmune anemia (low hemoglobin resulting in patient becoming pale and tired), and autoimmune thyroid problems are examples of such problems that can occur in people with leaky SCID.

In most cases, the treatments are similar to patients with classical SCID, and can include intravenous immunoglobulin, antibiotics, antifungals, specific treatments against the autoimmune complications (eg, IVIg for autoimmune thrombocytopenia) and ultimately, blood and marrow transplantation.

Doctors have long recognized that some infants will present with features of classical SCID (for example, serious bacterial, viral, or fungal infections, often involving the lungs resulting in trouble breathing or the gastrointestinal tract causing diarrhea and weight loss – features that suggest the immune system is not working properly), but also with other features that suggest the immune system is overacting (working too well). Infants with Omenn syndrome have features that suggest the immune system is not working, and on the other hand, also overacting, all at the same time.

Features that suggest the immune system is overacting include (1) a severe skin rash that often covers most of the body (sometimes called “generalized erythroderma” or “pachydermatitis”). This can look like a bad sunburn. Often infants with Omenn syndrome do not have hair or eyebrows because of this severe skin rash. (2) Enlarged lymph nodes (glands that can be felt in the neck, armpits, and groin) (3) Enlarged liver and spleen (organs found inside the abdomen). The liver and spleen should normally be under the rib cage and difficult to feel, but when enlarged, can be felt by the doctor during an abdominal examination. Some infants with Omenn syndrome will have all of these features, whereas others will only have some of them.

Yes, in that it describes an infant with severe combined immune deficiency who also has features of an overacting immune system. In all cases, however, Omenn syndrome has an underlying cause. There are a number of potential underlying causes of Omenn syndrome, however, only about 50% of the time are doctors able to figure out what this cause is. If no underlying cause can be found, the patient is diagnosed with Omenn syndrome. If an underlying cause is found, the patient is diagnosed with Omenn syndrome due to whatever the cause is.

A number of genetic mutations that also cause classical severe combined immune deficiency have also been found in Omenn syndrome. These include RAG1, RAG2, adenosine deaminase deficiency, ARTEMIS, and DNA Ligase IV (and this list is not complete). Other disorders that have been associated with Omenn syndrome include cartilage hair hypoplasia (short, hair abnormalities, skeletal abnormalities), CHARGE syndrome (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital abnormalities, ear abnormalities including deafness) and DiGeorge syndrome (low calcium, low parathyroid hormone levels, heart defects). Your doctor will look for other problems that may help to explain why Omenn syndrome has developed.

SCID is a group of congenital disorders (disorders present at birth), in which affected infants fail to develop T-cells, a critical component of the immune system. As a result of severe infections, the condition can be fatal in infancy, unless treated with bone marrow transplantation, enzyme replacement therapy or gene therapy. SCID infants should be isolated from infections as soon as possible. Costs for treatment are usually lower if a child is diagnosed within the first 3 1/2 months of life before major infections develop. The diagnosis of SCID very early in life is a true pediatric emergency.

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 75 individuals per year. SCID is a rare condition, but is as frequent as some conditions that newborns are currently tested for, such as biotinidase deficiency or certain metabolic disorders. This number does not account for deaths from undiagnosed SCID-related infections. The actual number of cases may be higher.

Clinical diagnosis is difficult without positive family history of SCID, or characteristic infection history. Blood tests for SCID typically reveal significantly lower-than-normal levels of T cells and a lack of germ-fighting antibodies. Genetic testing generally provides with specific diagnosis.

The most effective treatment for SCID is transplantation of blood-forming stem cells in the form of a blood and marrow transplant (either from bone marrow, peripheral blood stem cells, or umbilical cord blood stem cells). Blood forming stem cells can renew themselves as needed and produce a continuous supply of healthy immune cells. A bone marrow transplant from a 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 suitably matched donor are often performed.

If the presence of SCID in the family’s history is known, and the type of SCID genetic mutation has been identified, prenatal testing can be performed. Sequencing DNA from the fetus can be tested in an at-risk pregnancy via chorionic villus sampling (CVS) by removing and testing cells from the placenta or by amniocentesis in which a sample of the fluid surrounding the baby is removed and tested. Even when the gene mutation is not known, the diagnosis can be made in the fetus by sampling a small amount of fetal blood at around 18-20 weeks of gestation.

The sooner a child is diagnosed, the sooner treatment can begin and the more likely it is to be effective. Recent research shows that blood and marrow transplants in the first three months of life work better than transplants at a later age. It is critical to identify affected children immediately after birth in order to reduce their risk of exposure to life-threatening infection, and to improve the effectiveness of treatment. This is the major reason why many states have now started to perform newborn screening for SCID. Diagnosing patients in the first couple of weeks of life, before the onset of serious infections, can result in the patient getting to blood and marrow transplant sooner and ultimately having a better chance of survival.

If diagnosis is late, even after a successful bone marrow transplant, a patient may still have persistent health problems although this is not always the case and many children who are treated beyond 3 months of age do well. Most parents and physicians agree that ongoing health issues are not a result of the SCID itself, but because of the organ damage caused by multiple serious infections before diagnosis.