• Severe Combined Immunodeficiency (SCID)
  • Wiskott-Aldrich Syndrome
  • Chronic Granulomatous Disease
What is Severe Combined Immunodeficiency (SCID)?

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?

Who gets 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 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).

How is SCID Diagnosed?

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.
What is the treatment for SCID?

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.
What are the treatments for 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 (e.g. IVIg for autoimmune thrombocytopenia) and ultimately, blood and marrow transplantation.

Frequently Asked Questions
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.
What is Wiskott-Aldrich Syndrome (WAS)?

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.

What causes WAS?

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.

Who gets 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.

How is WAS Diagnosed?

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,
What is the treatment for WAS?

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.
Frequently Asked Questions
The lower platelet count predisposes the patient to spontaneous bleeding and prolonged, severe bleeding with injuries. Care should be taken to prevent injuries as much as possible. A helmet is recommended for infants and children when they becoming are actively mobile. Contact sports should be avoided, and the activities of the individual patient are best determined by the physician and the parents. A medical alert bracelet indicating that the patient has low platelets is recommended, as this can help patients receive prompt and appropriate care.

There are a few ways in which the platelet counts can be increased:

  • Transfusions: A platelet transfusion can increase the platelet counts for several days. Platelet transfusion can be used to control moderate to severe bleeding. It is also used to control a bleed that is not/cannot be controlled by other methods. Platelet transfusion may be used prior to surgery to improve the counts and prevent excessive bleeding during the surgery and during the recovery period. In general, it is better to keep platelet transfusions to a minimum and use other means to control the bleeding if possible.
  • High dose IVIG: Platelet counts may increase is some patients who are given high doses of IVIG. If there is significant improvement, IVIG is given every 3-4 weeks to keep the platelet counts up.
  • Medications: Patients with WAS can develop immune mediated thrombocytopenia (ITP, where thrombocytopenia means low platelets) where their immune system destroys their own platelets. Medications that are used for these patients include steroids such as prednisone, high dose IVIG and rituximab. These can help control the immune reaction and increase the platelet counts.
What is Chronic Granulomatous Disease (CGD)?

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).
Who gets CGD?

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.

How is CGD Diagnosed?

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.

What is the treatment for CGD?

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.
Frequently Asked Questions
Women with CGD can become pregnant and have babies without adverse effects to their health. Some of the drugs used to treat the infections common in patients with CGD can be passed from a pregnant woman to her baby, and may cause birth defects or miscarriage. However, there are alternatives that are safe to use in pregnancy. Women with CGD should discuss plans for alternative medication with her doctor prior to becoming pregnant.

The chance a parent who is affected by CGD will transmit CGD to their own children varies considerably with the type of CGD involved (X linked or autosomal recessive) as well as the sex of the parent.

Men with x-linked CGD have a 100% chance of having a baby girl who is a carrier of CGD (i.e. not affected by CGD, but the baby girl could pass the gene on to her sons or daughters with the next generation). A man with x-linked CGD will not have a girl affected by CGD, unless in the rare situation that the mother is also a carrier for x-linked CGD. Since CGD is a rare condition, it would be unusual for a mother to be a carrier and a father to have x-linked CGD. A man with x-linked CGD will not transmit the gene to any of his baby boys.

Men and women with autosomal recessive CGD have a 100% chance of their baby boys and girls being at least carriers. As long as the other parent (1) is not affected by CGD and (2) is not a carrier for the same genetic mutation, the children will not be affected by CGD (although all will be carriers). If the other partner is also a carrier for autosomal recessive CGD, there is a 50% chance the child (regardless of whether a boy or a girl) will be affected by CGD and a 50% chance the child will be a carrier. If the other partner also has two genetic mutations resulting in autosomal recessive CGD, then 100% of the offspring will be affected by CGD.

For women who are carriers of x-linked CGD (often this is tested for in a woman because a brother or uncle was affected by x-linked CGD), 50% of her girls will be carriers and 50% of her girls will not be carriers. None of the mother’s baby girls will be affected by CGD. However, 50% of her boys will be affected with CGD.

Autosomal recessive CGD is more common in populations where partnerships between men and women are more closely related from a genetic perspective, such as in cultures where marriage between close relatives is customary. Sometimes children can also be born with CGD where it is not apparent that a family history was present. In these situations, new mutations have arisen and these children will have the same risks of transmitting the gene to their own offspring in the future.

Mothers of males with CGD may be carriers of the X-linked form of CGD. Carrier status can be determined by a blood test. Often carrier mothers are healthy, although in some cases they may be prone to recurrent mouth ulcers or skin disorders.
  • Frequent and difficult-to-clear skin infections, such as abscesses, chronic nasal infection, boils, eczema, and impetigo
  • Joint infections
  • Pneumonia
These infections occur often, and may be difficult to heal.
Many people with CGD can carry on normal daily activities. Patients and their families should expect, and be prepared for, frequent and sometimes long stays in the hospital that may interfere with school or work.
Some children with CGD may grow and develop more slowly than peers. There is, also, the possibility that children who have received prolonged courses of steroids or who have been very ill for a long time, may not reach the their full height when they get older. Consulting an endocrinologist (doctor who specializes in growth and the way hormones work) may be appropriate.
Frequent episodes of being ill, serious infections, and prolonged hospital admissions may be stressful for patients and their families. Patients with CGD and their families may benefit from working with a social worker or a clinical psychologist for support.

RDCRN Contact Registry
Learn about all the benefits of joining the RDCRN Contact Registry.

Join Now