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Wiskott-Aldrich Syndrome and Transplant

Wiskott-Aldrich syndrome (WAS) is an inherited immune system disorder that can lead to frequent infections and problems with bleeding too easily. WAS occurs only in males and appears mostly in children but sometimes does not appear until adulthood. About 4 out of every 1 million boys born in the United States has WAS.

Causes of Wiskott-Aldrich syndrome

Inherited immune disorders are also called primary immune deficiency disorders. These disorders are caused by a mutation (mistake) in a gene that affects the immune system. A gene is an inherited code of instructions that tells the body how to make every cell and substance in the body.

The mutation that causes WAS affects a gene on the X chromosome, which comes from the mother. Disorders inherited on the X chromosome appear only in males. A female with the mutated gene will not have the disease but will be a carrier. This means she may pass the mutated gene on to her children.

In most cases, no one knows what causes the mutation to appear the first time. Once a mutation appears, it can be passed from mother to child through many generations.

In boys with WAS, the gene mutation affects the body's ability to make certain types of white blood cells that help the immune system fight infection. It also affects the body's ability to make platelets, blood cells that help control bleeding. Boys with WAS have fewer platelets than normal (thrombocytopenia). The platelets are also smaller than normal.

WAS and the immune system

The immune system is made up of organs and cells that work together to protect the body from infection and disease. The immune system uses white blood cells to fight infections. The white blood cells mark and attack cells that they do not recognize as belonging in the body.

There are several types of white blood cells, each with its own role. In boys with WAS, there are too few of two types of white blood cells called lymphocytes. The types of lymphocytes affected are:

B cells — B cells make antibodies. Antibodies attach to foreign cells and mark them to be attacked.
T cells — T cells direct B cells to make antibodies against foreign cells. T cells direct the rest of the immune system when to attack or stop attacking foreign cells. They also help in the attack.

Symptoms and diagnosis of Wiskott-Aldrich syndrome

Common signs and symptoms of WAS usually appear soon after birth or within the first year of life:

Bleeding easily because of too few normal platelets. This may include tiny red spots under the skin (petechiae), bruises, blood in bowel movements, bleeding gums and nose bleeds.
Frequent infections because of too few B cells and T cells. Common infections are ear and sinus infections and pneumonia.
Eczema (an itchy rash) of the skin.

These symptoms occur in the classic, severe form of WAS. About one-third of boys with WAS have the classic form. Other boys have a milder form of WAS and do not have all these symptoms.

Over time, some boys with WAS may have autoimmune problems, which means the immune system fights against the boy's own body. A common problem is anemia caused by the body destroying its own red blood cells. Older boys and adults with WAS also have a high risk of developing lymphoma, a type of cancer.

Diagnosis of WAS

To diagnose WAS, a doctor will do a blood test. In boys with WAS, the blood will show low numbers of platelets. The platelets that appear will be smaller than normal. In boys older than 2 years, tests of blood and skin cells will show problems with immune system functions. To be certain of the diagnosis, a doctor can also do a genetic test to look for a mutation of the gene that is linked to WAS.

Families affected by WAS may want to talk with a genetic counselor about family planning and the chances of having children with the disorder. In a family already affected by WAS, a test for the WAS gene mutation can be done during pregnancy (prenatal testing). An early diagnosis can enable early treatment and improve a child's chances of a good outcome.

Treatment of Wiskott-Aldrich syndrome

Boys with WAS are at risk of dying during childhood from infections, bleeding or lymphoma. However, with good supportive care, some boys with milder forms of WAS can live into adulthood. The only treatment that can cure WAS is a bone marrow or cord blood transplant (also called a BMT).

Supportive care

Supportive care is treatment to manage symptoms and help patients live with a disease. Supportive care does not cure the disease. Supportive care treatments for boys with bleeding problems (thrombocytopenia) may include:

Platelet and/or red blood cell transfusions.
Intravenous immune globulin (IVIG).
A type of medicine called corticosteroids.
Removing the spleen (splenectomy). A splenectomy may lead to an increase in the number of platelets, but it also increases the risk for serious blood infections (sepsis). To prevent sepsis, boys who have had a splenectomy may need treatment with antibiotics any time they get a fever.

Treatments to protect boys with WAS from infection may include:

Watching closely for infections and treating them quickly.
Treatment with antibiotics and/or IVIG to prevent infections before they occur.

Transplant for Wiskott-Aldrich syndrome

The only treatment that can cure WAS is a bone marrow or cord blood transplant (also called a BMT). A bone marrow or cord blood transplant replaces the abnormal cells in the bone marrow with healthy blood-forming cells from a family member or unrelated donor or cord blood unit. The healthy cells can come from the bone marrow or peripheral (circulating) blood of an adult donor or from the blood collected from the umbilical cord after a baby is born. The transplanted blood-forming cells will make normal platelets, T cells and B cells for the body.

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 match. However, since WAS is inherited, many children with WAS do not have a healthy matched sibling. For children without a suitable sibling donor, doctors may search the National Marrow Donor Program (NMDP) Registry for a suitable adult donor or cord blood unit. For boys age 5 and younger, transplants using unrelated donors have had similar outcomes to those using matched siblings.

If no suitable sibling or unrelated donor or cord blood unit is available, doctors may use one of the child's parents or other family members as a donor. Each parent's tissue type matches half of the child's tissue type (a haploidentical match). For some inherited immune disorders, such as severe combined immunodeficiency (SCID), haploidentical donors have had good results. However, for boys age 5 and younger, the outcomes of haploidentical transplants have been much lower than those for transplants using matched siblings or unrelated donors.

Factors that affect WAS transplant outcomes

A transplant can offer a cure to some boys with WAS, but it has serious risks and may not be a treatment option for all patients. A boy's age at transplant affects his likelihood of survival. The likelihood of survival is highest in boys 5 years of age and younger. How closely the donor matches the patient is also an important factor in transplant outcomes.

WAS transplant outcomes

It is a good idea to ask your doctor for help interpreting these data and any other survival outcomes data you find. Your doctor can provide context for these data and discuss your specific situation with you. For more things to consider, see Understanding Survival Outcomes Data.

A study of outcomes for 170 boys who received a transplant for WAS between 1968 and 1996 showed the importance of both the age of the patient and the donor selected. [1] The best outcomes were found in boys who were 5 years of age or younger when they received a transplant.

Boys who had matched siblings as donors also had better outcomes than those with other donors. However, for boys who were 5 years of age or younger, outcomes were similar using matched sibling donors and unrelated donors.

Probability of survival at five years after transplant by age of patient and type of donor [1]
Age of Patient	Matched Sibling Donor	Unrelated Donor	Other Related Donors (not matched and/or not a sibling)
All ages	87% (55 patients)	71% (67 patients)	52% (48 patients)
5 years or younger	90% (41 patients)	84% (52 patients)	53% (41 patients)
Older than 5 years	79% (14 patients)	0% (15 patients)	38% (7 patients)

Many of the long-term survivors were cured of their disease. About 75% of survivors who had matched sibling or unrelated donors were cured, with most others showing improvement. However, only about 57% of survivors who had a related donor other than a matched sibling were cured.

Other smaller studies have also shown high long-term survival rates after transplants from matched related donors. These studies included eight to 10 patients and had survival rates of 80% to 91%. [2,3,4]

Other studies have also shown that for boys 5 years of age or younger, transplants using unrelated donors or cord blood units can offer a likelihood of survival nearly as high as those for transplants using matched sibling donors. Between 1998 and 2006 the National Marrow Donor Program (NMDP) facilitated 48 transplants using unrelated donors for boys with WAS (Figure 1). The 5-year survival rate was 80%. Forty-one of these boys were 5 years old or younger, and seven were older.

Figure 1.
Wiskott-Aldrich Syndrome: Survival of pediatric (age <18 years) marrow recipients with all preparative regimens, unrelated donor transplants facilitated by the NMDP, 1998 - 2006. (NMDP data)

View Larger Version How to read this figure

Making treatment decisions

If your child has Wiskott-Aldrich syndrome, it is important to see a doctor who is an expert in the disorder. If your primary doctor has not treated other patients with WAS, ask him or her to refer you to an expert for consultation.

A doctor who is an expert in WAS can recommend the best treatment and explain the possible risks. A transplant has serious risks and is not an option for all children, but it can offer some children with WAS the chance for a cure and a longer life.

It is important to talk with your doctor about the risks of transplant compared to the risks of continuing supportive care. Some boys with milder symptoms can have a good quality of life for many years with supportive care treatments. For boys with severe WAS who are 5 years of age or younger, a transplant may be the first treatment choice. Transplants for younger boys have high rates of success using either matched sibling donors or unrelated donors or cord blood units. For older boys or boys with less severe forms of WAS, other treatments may also be considered. Your doctor can discuss treatment options and potential benefits and risks with you based on your child's specific situation.

More information on Wiskott-Aldrich syndrome

You can get more information about WAS from disease-specific organizations, such as:

National Primary Immunodeficiency: The Wiskott Aldrich Syndrome: http://www.info4pi.org/patienttopatient/index.cfm
?section=patienttopatient&content=syndromes&area=14&
CFID=12977514&CFTOKEN=62075299
Immune Deficiency Foundation: About Primary Immune Deficiencies (follow link for printable PDF file about WAS): http://www.primaryimmune.org/pid/whatis_pid.htm

For other organizations that offer information and resources, see Organizations That Can Help: A Searchable Directory.

References

Filipovich AH, Stone JV, Tomany SC, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001; 97(6):1598-1603.
http://www.bloodjournal.org/cgi/content/full/97/6/1598
Rimm IJ, Rappeport JM. Bone marrow transplantation for the Wiskott-Aldrich syndrome. Long-term follow-up. Transplantation. 1990; 50(4):617-620.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve
&db=pubmed&dopt=Abstract&list_uids=2219285&query_hl=13
Brochstein JA, Gillio AP, Ruggiero M, et al. Marrow transplantation from human leukocyte antigen-identical or haploidentical donors for correction of Wiskott-Aldrich syndrome. J Pediatr. 1991; 119(6):907-912.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve
&db=pubmed&dopt=Abstract&list_uids=1960605&query_hl=9
Ozsahin H, Le Deist F, Benkerrou M, et al. Bone marrow transplantation in 26 patients with Wiskott-Aldrich syndrome from a single center. J Pediatr. 1996; 129(2):238-244.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve
&db=pubmed&dopt=Abstract&list_uids=8765621&query_hl=6
&itool=pubmed_docsum
Small TN, Friedrich W, O'Reilly RJ. Hematopoietic cell transplantation for immunodeficiency diseases. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas' Hematopoietic Cell Transplantation. 3rd ed. Malden, Mass: Blackwell; 2004:1430-1442.