Severe combined immunodeficiency (SCID) is a serious medical condition. Children born with SCID lack adequate immune protection against bacteria, viruses, and fungi and are prone to infections that would not normally cause illness in a person with intact and functional immune system.

Children with SCID are usually diagnosed within the first year of life due to the high frequency and severity of infections. Some of the common organisms that cause mild or no illness in children with healthy immune systems can cause severe infections in children with SCID.

Children affected by SCID can also become ill from live viruses present in some vaccines. These vaccines (such as Chickenpox, Measles, Rotavirus, oral polio and BCG, etc.) contain viruses and bacteria that are weakened and don’t harm children with a healthy immune system. In patients with SCID however, these viruses and bacteria may cause severe, life-threatening infections.

With the introduction of newborn screening for SCID in a number of states in the United States and in Ontario in Canada, young infants are increasingly being diagnosed with SCID soon after birth, before the onset of serious infections. The PIDTC has confirmed that one of the most important predictors of how well an infant with SCID will do after a blood and marrow transplant is whether or not they have a serious infection before transplant. Infants who are diagnosed early by newborn screening can receive a blood and marrow transplantation (BMT) at a very young age (often 1-3 months of age) with the goal of having a more successful transplant.

What is “Leaky” Severe Combined Immune Deficiency?

What is Omenn Syndrome?

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 1 out of every 58,000 births. (Kwan et al. Newborn screening for severe combined immune deficiency in 11 screening programs in the United States. Journal of the American Medical Association (2014) 312: 729-738).

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 PEG-ADA) 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, PEG-ADA 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.

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 (e.g. IVIg for autoimmune thrombocytopenia) and ultimately, blood and marrow transplantation.

Wiskott-Aldrich Syndrome (WAS) is a serious medical condition that causes problems both with the immune system and with blood clotting. Patients with WAS may be very susceptible to infections caused by bacterial and fungal organisms. Many patients also have a moderate to severe eczema (red, scaly skin rash). Finally, patients with WAS can experience easy bruising and bleeding. This is because people with WAS have low numbers of small, non-functional platelets, the cells in the blood that clump together to form blood clots.

Children with WAS are diagnosed most commonly in the first 1-2 years of life because of easy bruising, abnormal bleeding, or low platelet counts. Patients may also have severe or frequent infections, including bacterial ear infections, sinus infections, pneumonia, blood infections, or viral infections.

Patients show a wide variation in the severity of the disease Four types have been identified:

1. Classic or Severe WAS: This is the most severe form of WAS.
2. X-Linked Thrombocytopenia (XLT): This is milder form of WAS where the platelets are affected but there is little or no immunodeficiency. Sometimes the symptoms of WAS and XLT overlap, making the distinction between the two unclear.
3. Intermittent Thrombocytopenia: The mildest form called where the platelet abnormalities are intermittent and there is no immunodeficiency.
4. X Linked Neutropenia: This is the rarest form in which the platelets are normal but there is a serious defect in the neutrophils (a kind of white blood cell). Patients can have serious and recurrent infections.

Symptoms of WAS vary among patients. Individuals with classic WAS may have bleeding, frequent infections, eczema and often develop autoimmune disorders or malignancy. Individuals with XLT may have just bleeding manifestations or may have eczema. The symptoms typically present at birth or in infancy.

WAS is caused by a mutation in the WAS gene that is located on the X chromosome. The production of the WAS protein is controlled by the WAS gene. This gene instructs cells to make the WAS protein. When this gene is mutated, it results in patients having abnormal, reduced or absent protein causing WAS.

WAS is an X-linked disorder. In X-linked disorders, females may carry the gene for the disorder but don’t develop symptoms, whereas boys develop the clinical problems associated with the disease. WAS is estimated to occur in approximately 1 out of every 100,000 boys. For more information click here.

The diagnosis of WAS should be considered in any boy with unusually increased bruising or bleeding, particularly if it was noticed soon after birth or in infancy. Additional criteria include recurrent bacterial, viral infections in infancy and early childhood, eczema, the presence of autoimmune disorders or lymphoma. There may be a family history of similar symptoms among brothers, cousins or maternal uncles.

Once the diagnosis of WAS is clinically considered, the following laboratory tests may be ordered:

• Complete Blood Counts (CBC with differential) –This test includes the count and size of platelets. WAS patients present with platelet size that is significantly smaller than normal.
• Immunoglobulin levels (IgG, IgM, IgA, IgE) – Immunoglobulins (antibodies) levels in blood may be low in WAS
• Specific antibody titers. These tests may detect decreased antibody response to vaccines, in particular to the Pneumovax, and low levels of antibodies to red cells (isohemagglutinins) normally present in all people
• WAS protein levels in white blood cells: Absent, decreased or abnormal intracellular WASP in the white blood cells is also used as a screening tool for early diagnosis of WAS.
• Specific genetic testing - Confirmation of the diagnosis of WAS is done by testing for mutations in the WASP gene on the X chromosome,

When a boy has been diagnosed with WAS, there are several possible treatment options. Physicians and parents choose different treatment options according to the severity of the diseases. Physicians review individual cases and make recommendations on the treatment options that are most suitable

Treatment for WAS 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.
• Using a helmet to reduce the risk of head trauma and intracranial hemorrhage
• Avoid nonsteroidal anti-inflammatories such as Ibuprofen (Motrin, Advil) or Aspirin (ASA) that can further impair platelet function.
• Use immunoglobulin supplementation (IVIg) when specific antibody responses are not developed
• A blood and marrow transplantation is the only proven cure for WAS. Other measures primarily provide relief from symptoms and decrease the risk of infections. Many physicians recommend that patients with Classic WAS undergo a transplant as early as possible. Transplant has the best success rate if it is done early in life with a well-matched donor.
• Research clinical trials involving gene therapy for WAS may be available. Discuss with your doctor to determine if this is something you / your child may be eligible for. At this time, gene therapy for WAS is considered experimental and not a standard treatment.
• The management of patients with XLT is less clear and the decision to transplant or not is debated by the experts. Currently, some patients with XLT undergo a transplant whereas others opt for more conservative treatment.

Chronic Granulomatous Disease (CGD) is an inherited condition characterized by a defect of specific white blood cells called neutrophils. Neutrophils are important for the killing of bacterial and fungal infections. In CGD, the neutrophils are unable to make the hydrogen peroxide needed to kill bacteria and fungi. Patient with CGD are, therefore, highly susceptible to infections from certain bacterial and fungal organisms. Patients with CGD have normal immunity to other microbes, including viruses. As a result, patients with CGD have normal immunity against common infections like the common cold or stomach flu (the majority of which are caused by viruses).

Children with CGD are usually healthy at birth; however, they typically develop serious bacterial and fungal infections in early childhood that are difficult to treat. Patients may have severe or frequent infections including:

• Bacterial ear infections, pneumonia, or blood infections
• Bone infections
• Skin or liver abscesses
• Fungal pneumonia

Individuals with CGD can also develop a number of complications that are related to the immune system trying (ineffectively) to deal with bacterial and fungal infections. Large numbers of inflammatory cells (neutrophils and macrophages that do not work) can “clump” together into larger masses known as granulomas. This is why the condition is known as Chronic Granulomatous Disease. These granulomas are not effective at killing bacteria and fungi, become long-standing and can last for months to years, and can cause problems for patients with CGD. These complications are often known as the “inflammatory” complications of CGD. Problems can include:

• Persistent vomiting from granulomas obstructing the ability of the stomach to empty.
• Difficulty voiding (peeing), often with pain, because of granulomas obstructing the outflow from the bladder. Sometimes, granulomas develop in the ureters. Both of these situations can lead to a backflow of urine into the kidneys (hydronephrosis) which over time can lead to kidney problems if not dealt with.
• Mouth sores from small granulomas in the mouth.
• Severe diarrhea and weight loss due to granulomatous colitis. This can look very similar to a patient with Crohn’s disease (a type of inflammatory bowel disease).

CGD can affect either boys or girls of any race or ethnicity. Defects in each of five distinct genes have been reported to result in CGD. The most common form (about 80% of cases) occurs in boys and is inherited as an X-linked disease, meaning that females may carry the abnormal gene for the disorder but don’t develop symptoms, whereas boys develop the clinical problems associated with the disease. The other four forms of CGD are inherited as an autosomal recessive disorder, meaning that the patient has one defective gene inherited from each parent. CGD is estimated to occur in approximately 1 out of every 250,000 live births. The average age at diagnosis is 3 years for boys and 7 years for girls.

Frequent respiratory and skin infections suggest the possibility of CGD, especially if the infections are caused by certain bacteria or fungi, such as Serratia and Aspergillus. Definitive diagnosis of CGD is made by testing the production of hydrogen peroxide by neutrophils, and is confirmed by gene sequencing analysis to identify disease-causing mutations in any of the genes that are responsible for this condition.

Treatment for CGD may include the following:

1. Medications: Medications should be prescribed to both prevent and treat bacterial and fungal infections. Standard of care includes the use of an antibiotic known as trimethoprim-sulfamethoxazole (also known as co-trimoxazole, Septra) and an anti-fungal medication (common ones used include itraconazole, voriconazole, and posaconazole). These medications should be taken every day to prevent bacterial and fungal infections. Note that fluconazole, a common anti-fungal used to treat yeast infections, is not sufficient for anti-fungal prevention in patients with CGD.
2. Despite the use of preventative medications, infections can still occur. Signs such as fevers, skin redness, cough, difficulty breathing, and extreme tiredness may signify an underlying infection and medical attention should be sought. Additional antibiotics and antifungals may be needed.
3. Corticosteroids (steroids such as prednisone, methylprednisolone and dexamethasone) may be needed to treat the inflammatory / granulomatous complications of CGD, most notably the gastrointestinal disease (colitis).
4. In addition, your doctor may recommend a medication known as interferon-gamma, although its use is not universal and some doctors will wait to prescribe this only in certain situations.
5. Avoiding infection-causing substances - Since severe infections in CGD can be caused by organisms present in the environment, patients with CGD are often encouraged to avoid areas with visible mold, including places containing woods and mulch.
6. Blood and Marrow Transplantation (BMT) - provides patients with CGD with a functioning immune system capable of protecting them from infections. BMT replaces the defective cells with normally functioning cells from a healthy donor. BMT has been effective in many patients, especially if done before major organ damage occurs and in the absence of active infection.
7. Gene therapy to correct the genetic mutation in CGD is still in experimental stages and is still considered an investigational treatment option.