Wiskott–Aldrich syndrome (WAS), Eczema-Thrombocytopenia-Immunodeficiency Syndrome

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich’s original description in 1954.The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.

Wiskott-Aldrich syndrome is a condition that affects blood cells and cells of the immune system.  This condition is seen almost exclusively in males.  Individuals with this condition have microthrombocytopenia, which is a decrease in the number and size of blood cells involved in clotting (platelets).  This platelet abnormality, which is typically present from birth, can lead to easy bruising or episodes of prolonged bleeding following minor trauma.  Eczema, an inflammatory skin disorder characterized by abnormal patches of red, irritated skin, often occurs in people with this condition.  Affected individuals also have an increased risk of infection due to dysfunction of many types of immune cells, such as T cells, B cells, dendritic cells, and natural killer cells.  Some people develop autoimmune disorders, which occur when the immune system malfunctions and attacks the body’s tissues and organs by mistake.  The risk of developing some types of  cancer, such as cancer of the immune system cells (lymphoma), is increased in people with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) was first described by Wiskott in 1937 and was further characterized by Aldrich in 1954. It is an X-linked recessive immunodeficiency disorder characterized by the triad of recurrent bacterial sinopulmonary infections, eczema (atopiclike dermatitis), and a bleeding diathesis caused by thrombocytopenia and platelet dysfunction. However, only a third of patients with the syndrome have the classic triad.Almost 90% of patients have manifestations of thrombocytopenia at presentation, 20% have only hematologic abnormalities, 5% have only infectious manifestations, and none have only eczema.Other symptoms may include autoimmune phenomena and malignancies

The syndrome is named after Dr Robert Anderson Aldrich (1917–1998), an American pediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937. Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006 a German research group analysed family members of Wiskott’s three cases, and surmised that they probably shared a novel frameshift mutation of the first exon of the WAS gene.

Wiskott-Aldrich syndrome occurs in males but can occur in females when the X chromosome that contains the functional allele is inactivated, although this is rare. There may be multiple revertant genotypes in patients with Wiskott-Aldrich syndrome.[4]

The gene for the Wiskott-Aldrich syndrome protein (WASp) is localized to Xp11.22-23 and consists of 12 exons that encode a 502 amino acid (53 kD) protein. WASp is a cytosolic protein expressed on all hematopoietic cell lineages and is essential for normal antibody function, T-cell responses, and platelet production.It also regulates actin polymerization, transcription, and a selective, post-transcriptional role in Th2 effector function.About 300 mutations have been found throughout the gene and can include base pair substitutions, insertions, and deletions. These mutations can result in different clinical phenotypes, including classic Wiskott-Aldrich syndrome, X-linked thrombocytopenia, intermittent thrombocytopenia, and neutropenia.The type of specific mutation, its location within the gene, and its effect on protein expression appear to determine an individual patient’s clinical phenotype

Causes

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 protein 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.

The WASP gene is located on the Xp11.22-23 region of the X chromosome and is inherited in a sex-linked fashion. A male child of a female carrier has a 50% chance of being affected; a female child has a 50% chance of being a carrier. Theoretically, female carriers of WASP mutations could have clinical illness if extreme lyonization occurs, but nonrandom X inactivation is characteristic for carriers. Wiskott-Aldrich syndrome is caused by various mutations in the gene that code for the WASp. This mutation is expressed in hematopoietic cells (eg, lymphocytes) and impairs the normal function of WASp in actin polymerization.Eczema appears to be related to the abnormal function of the T cells.

Mutations in the WAS gene cause Wiskott-Aldrich syndrome.  The WAS protein (WASP) is found in cells made from hematopoietic stem cells, including blood cells and certain immune cells.  This protein is involved in relaying signals from the cell surface to the actin cytoskeleton, which is a network of fibers that make up the cell’s structural framework. The actin cytoskeleton has several critical functions, including determining cell shape and allowing cells to move.

WAS gene mutations impair WASP’s role in cell signaling and disrupt the function of the actin cytoskeleton in certain immune cells and blood cells.  Immune cells that lack WASP function tend to have trouble responding to factors that trigger cell growth and division (proliferation).  Additionally, these defective cells have problems with cell movement (motility) and difficulty attaching to other cells (cell adhesion).  These disruptions in normal immune cell function contribute to eczema and the increased risk of infection, autoimmune disorders, and lymphoma associated with this condition.   Impaired WASP function also interferes with normal platelet development, causing microthrombocytopenia, the characteristic sign of Wiskott-Aldrich syndrome.

Mutations can occur in any of the 12 exons of the WASP gene. Approximately one half of the reported mutations are single-base pair substitutions, often within CpG dinucleotide hot spots. Half of the mutations have been identified within the first 3 exons. Milder disease has been reported for mutations in exons 1 and 2.

A strong phenotype-genotype correlation was discovered, with classic Wiskott-Aldrich syndrome occurring when WASp is absent, X-linked thrombocytopenia occurring when mutated WASp is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site; however, exceptions are noted.

Signs and symptoms

Due to its mode of inheritance, the overwhelming majority are male. The first signs of WAS are usually petechiae and bruising, resulting from thrombocytopenia (low platelet counts). Spontaneous nose bleeds and bloody diarrhea are common. Eczema develops within the first month of life. Recurrent bacterial infections develop by three months. Splenomegaly is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorder, and malignancies (mainly lymphoma and leukemia) develop in up to a third of patients.

IgM levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated.

The characteristic triad of bleeding, eczema, and recurrent infections generally become evident during the first year of life. However, only one third of patients with WASP mutations express the classic triad of Wiskott-Aldrich syndrome (WAS).

The first clinical signs are petechiae (see the image below) and ecchymoses of the skin and oral mucosa and bloody diarrhea. Patients may have prolonged bleeding after circumcision or from the umbilical stump. CNS bleeding occurs in fewer than 2% of patients but may occur at birth or later due to minor trauma. One series of 154 patients found petechiae or purpura in 78%, serious GI bleeding (hematemesis or melena) in 28%, epistaxis in 16%, and intracranial bleeding in 2% of patients.

This 1-year-old boy was hospitalized because of reThis 1-year-old boy was hospitalized because of respiratory syncytial virus bronchiolitis but was noted to have eczema and petechiae (note arrow). His history was significant for a subdural hematoma for which trauma was denied; at that time the platelet count was 212,000. His diagnosis of Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a missense mutation (Phe 128 Ser).

With the loss of maternally transported immunoglobulin G (IgG), infants begin to have infections, most commonly otitis media, at 4-8 months. Pneumonia, sepsis, and meningitis are caused by polysaccharide-coated bacteria, predominantly Streptococcus pneumoniae,Haemophilus influenzae type b (Hib), and Staphylococcus aureus.

Less commonly, gram-negative bacteria such as Klebsiella pneumoniae and Escherichia coli are etiologic agents for sepsis or meningitis. Viral infections may be unusually severe. Herpes simplex often causes mucocutaneous infections, and varicella-zoster virus may be life-threatening. Opportunistic infections such as Pneumocystis carinii have been reported but are rare. Fungal infections are usually restricted to mucocutaneous candidiasis.

Atopic symptoms are frequently present, and eczema develops in 81% of these patients.Eczema ranges from mild to severe, and patients usually present earlier than immunocompetent infants. The eczema may improve as the patient gets older, although serious complications such as secondary infection (eg, cellulitis, abscess) or erythroderma can occur.Milk and other food allergies have been associated with eczema in Wiskott-Aldrich syndrome. Eczema may worsen in the presence of infection; it also follows the typical pattern of worsening in the winter. Although the dermatitis often clinically mimics atopic dermatitis, it is generally more exfoliative. Conventional topical care with moisturizing creams and steroids have moderate benefit. Other atopic disorders, reactive airway disease (typically in toddlers), and allergic rhinitis (typically in school-aged children) are also common

Autoimmune disorders, particularly autoimmune hemolytic anemia (AIHA), can be observed in patients of any age. In some cases, infections seem to aggravate AIHA. Arthritis, nephritis, and immune thrombocytopenia and neutropenia are also increased in incidence.

Lymphomas and leukemias constitute most malignancies, although various other malignancies are reported. Patients can present in mid childhood. The risk of malignancy seems to increase with age. The most common malignancy is non-Hodgkin lymphoma.

Physical

Watch for signs of bleeding, infection, malignancy, and atopy during the physical examination. The patients’ general appearance and vital signs are important. Follow height and weight over time to monitor appropriate development. Patients usually experience normal growth for the first several years of life, even with episodes of severe acute infections

Examine the skin for any evidence of eczema. The face, scalp, and flexural areas are most commonly involved. Superficial or deep infections such as secondary bacterial infections (eg, impetigo, cellulitis, furuncles, abscesses), eczema herpeticum, and molluscum contagiosum are common. Also check the skin for purpura (thrombocytopenia). The presence of lower extremity ecchymoses in infants (see the image below) who are not yet walking indicates a platelet abnormality. Examine for bloody diarrhea in the absence of an infectious etiology. Other manifestations may include hematemesis, melena, epistaxis, and hematuria.

This 10-month-old infant presented with bloody diaThis 10-month-old infant presented with bloody diarrhea at age 4 months followed by recurrent otitis media infections. A maternal uncle had Wiskott-Aldrich Syndrome (WAS). Note the mild malar eczema and pretibial ecchymoses in this nonambulatory child. His diagnosis was confirmed by immunologic parameters, thrombocytopenia, and low platelet volume.

During head and neck examinations, note any abnormalities of the tympanic membranes (eg, otitis media) or sinuses and mucous membranes (eg, sinonasal infections, pharyngitis, thrush). The older infant often has a dramatically increased incidence of otitis media, although it responds appropriately to oral antibiotics.

Carefully auscultate the lungs to check for wheezing (eg, asthma) and rales or rhonchi (eg, pulmonary infection such as bronchitis or pneumonia).

Clinical signs of anemia, paleness, tachycardia, and even jaundice can be caused by blood loss or AIHA. Renal failure, presumably secondary to glomerulonephritis, should also be considered as a potential cause for anemia.

Investigate for a possible malignancy if adenopathy or hepatosplenomegaly is present.

Neurological examination is particularly relevant if meningitis, CNS lymphoma, or intracranial bleeding or infection is considered. Cutaneous vasculitis may be rarely seen as recurrent acute hemorrhagic edema of infancy.

Diagnosis

The diagnosis is made on the basis of clinical parameters, the blood film and low immunoglobulin levels. Typically, immunoglobulin M (IgM) levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. It must be remembered that not all patients will have a family history, since they may be the first to harbor the gene mutation. Often, leukemia may initially be suspected on the basis of the low platelets and the infections, and bone marrow biopsy may be performed. Decreased levels of Wiskott-Aldrich syndrome protein and/or confirmation of a causative mutation provides the most definitive diagnosis.

Sequence analysis can detect the WAS-related disorders of Wiskott–Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN). Sequence analysis of the WASp gene can detect about 98% of mutations in males and 97% of mutations in female carriers. Because XLT and XLN symptoms may be less severe than full WAS and because female carriers are usually asymptomatic, clinical diagnosis can be elusive. In these cases, genetic testing can be instrumental in diagnosis of WAS-related disorders.

Classification

Jin et al. (2004) employ a numerical grading of severity:

  • 0.5: intermittent thrombocytopenia
  • 1.0: thrombocytopenia and small platelets (microthrombocytopenia)
  • 2.0: microthrombocytopenia plus normally responsive eczema or occasional upper respiratory tract infections
  • 2.5: microthrombocytopenia plus therapy-responsive but severe eczema or airway infections requiring antibiotics
  • 3.0: microthrombocytopenia plus both eczema and airway infections requiring antibiotics
  • 4.0: microthrombocytopenia plus eczema continuously requiring therapy and/or severe or life threatening infections
  • 5.0: microthrombocytopenia plus autoimmune disease or malignancy

Pathophysiology

XlinkRecessive.jpg Xlinkrecessivefather.jpg

In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.

Wiskott–Aldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASp). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASp mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene.

The WASp gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex. In T-cell, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse.

WASP is a key regulator of actin polymerization in hematopoietic cells. As a cytoskeletal regulator, it is necessary for induction of normal immunity. WASp functions as a bridge between signaling and movement of the actin filaments in the cytoskeleton. WASp has several well-defined domains (pleckstrin, cofilin, verprolin, SH3) that are involved in signaling, cell locomotion, and immune synapse formation.

In vitro studies with T cells, platelets, phagocytes, and dendritic cells of patients with Wiskott-Aldrich syndrome reveal defects in the formation of microvilli, filopodia, phagocytic vacuoles, and podosomes, respectively; these structures depend on cytoskeletal reorganization of actin filaments. Researchers also identified many different mutations that interfere with the protein binding to Cdc42 and Rac GTPases, among other binding partners, most of which are involved in regulation of the actin cytoskeleton of lymphocytes.The actin cytoskeleton is responsible for cellular functions, such as growth, endocytosis, exocytosis, and cytokinesis.

Mutations of WASP are located throughout the gene and either inhibit or dysregulate normal WASp function. WASp facilitates the nuclear translocation of nuclear factor kappa-B (NF-kB) and was shown to play an important role in lymphoid development and in the maturation and function of myeloid monocytic cells. In mice, WASp was found to be essential for NF-ATp activation, and for nuclear translocation of p-Erk, Elk1 phosphorylation, and c-fos gene expression in T cells. These defects in mutated forms of WASP are the likely etiology of defective IL-2 expression and T-cell proliferation in Wiskott-Aldrich syndrome.

Clot formation is interrupted by impaired formation of fibrin strands. WASp binds to calcium and integrin binding protein (CIB) on platelets. The complex of CIB and mutated WASp reduces alpha2-beta3 integrin mediated cell adhesion and causes defective platelet aggregation, resulting in bleeding.

Research has shown phenotype-genotype correlation. Classic Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and X-linked neutropenia occurs when WASp is absent, when mutated WASp is expressed, and when missense mutations occur in the Cdc42-binding site, respectively. Although exceptions are noted and although predicting long-term prognosis based on these findings is difficult, this research may lead the way to curative hematopoietic stem cell transplantation and gene therapy.Further research is underway to identify WASp-associated proteins, such as WASp-interacting protein (WIP) and several Wiskott-Aldrich syndrome proteins verprolin homologous (WAVE).

The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized  (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T cells are unable to reorganize their actin cytoskeleton. The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp.Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk.

A defect in CD43 molecule has been found to be associated in patients with Wiskott–Aldrich syndrome.

Epidemiology

The estimated incidence of Wiskott-Aldrich syndrome is between 1 and 10 cases per million males worldwide. The combined incidence of WAS and XLT is about 4-10 in 1 million live births. There is no geographical factor. The estimated incidence of Wiskott-Aldrich syndrome in the United States is 1 in 250,000 live male births.

The frequency in the European population has been reported to be similar to that of the United States (1 in 250,000 live male births). A study from Switzerland reported the incidence of Wiskott-Aldrich syndrome is 4.1 cases per 1 million live births. The same study also examined the prevalence of Wiskott-Aldrich syndrome in several national registries (ie, Italy, Japan, Switzerland, Sweden) and found that this condition occurred in 2-8.8% of patients with primary immunodeficiencies.A similar range has been documented in a national registry in Ireland, as well.

Morbidity and mortality have gradually improved with better antibiotics, advances in blood banking, better supportive care, and the ability to successfully provide immune reconstitution by stem cell transplantation. Median survival has increased from 8 months in patients born before 1935 to longer than 6 years in patients born after 1964.In one case series, 94 surviving patients ranged in age from 1-35 years, with a median of 11 years; the average age of patients who died was 8 years.

In one study the reported cause of death among patients who did not receive bone marrow transplants were infection (44%), bleeding (23%), or malignancy (26%).Younger patients are more likely to die from bleeding, children are more likely to die from infection, and children and young adults die most often from malignancies. Malignancies may occur in children but are more frequent in affected adults. Lymphomas occur in 26% of patients aged 20 years and older. In one series, 12% of patients developed malignancies, primarily lymphoreticular tumors, and leukemia. In that series, the relative risk of malignancy was more than 100-fold that of normal and the risk increased with age.

The average lifespan for patients who do not receive immune reconstitution is the second to third decade of life, although patients have survived into the fifth decade of life. Following major histocompatibility complex (MHC)–matched stem cell transplantation, the patient who escapes graft versus host disease (GVHD) usually has completely normal immune function and, therefore, has an excellent prognosis for normal survival.Survival rates after stem cell transplant have continued to improve, particularly after more recent emphasis on performing these procedures as soon as possible after diagnosis.

Wiskott-Aldrich syndrome has been reported in individuals of European, African, and Asian ancestry; however, Blacks and Asians are less likely to be affected. One large series of 301 cases of Wiskott-Aldrich syndrome from 149 families reported that 8 families were black and 4 families were Chicano.Of the 40 families whose ancestry was traced outside North America, 38 emigrated from Europe.

More than 90% of affected patients are male, but females have been reported in the literature. Females typically have no family history. In some cases, females have been shown to have nonrandom inactivation of the X chromosome bearing the functional Wiskott-Aldrich syndrome allele.

Age at presentation ranges from birth to 25 years. In one review, the average age of presentation was 21 months.Male infants present at birth with petechiae and ecchymoses. Infections usually begin in early infancy after maternal immunoglobulin G (IgG) is lost during the first 3 months of life. The frequency of infections usually increase with age. Patients are especially susceptible to encapsulated organisms. Eczema develops during the first year of life and resembles classic atopic dermatitis. Malignancies may occur in children but are more frequent in affected adults. Lymphomas occur in 26% of patients aged 20 years and older.

Treatment

Treatment of Wiskott–Aldrich syndrome is currently based on correcting symptoms. Aspirin and other non-steroidal anti-inflammatory drugs should be avoided, since these may interfere with platelet function. A protective helmet can protect children from bleeding into the brain which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or a splenectomy. For patients with frequent infections, intravenous immunoglobulins (IVIG) can be given to boost the immune system. Anemia from bleeding may require iron supplementation or blood transfusion.

As Wiskott–Aldrich syndrome is primarily a disorder of the blood-forming tissues, a hematopoietic stem cell transplant, accomplished through a cord blood or bone marrow transplant offers the only current hope of cure. This may be recommended for patients with HLA-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.

Studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus have begun.Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome.Currently, many investigators continue to develop optimized gene therapy vectors.

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 can work with the National Marrow Donor Program® (NMDP) to search for a suitable adult donor or cord blood unit from our Be the Match Registry® and other registries worldwide. 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 poorer than those for transplants using matched siblings or unrelated donors.

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.

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

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% (7patients)

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%.

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 we 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

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