WAS: the Wiskott-Aldrich Sydrome

Author: Francesca De Lio
Date: 09/02/2014




The Wiskott-Aldrich syndrome is a rare inherited X-linked recessive syndrome due to mutations of the gene was, characterized by thrombocytopenia, small patelet size, eczema and recurrent infections.
X-linked thrombocytopenia is a variant of WAS which presents with a milder phenotype, generally limited to thrombocytopenia.
It is also classified as "combined immunodeficinecy" because it affects both B and T system.


This syndrome was first described in 1937 by Dr. Alfred Wiskott, a German pediatrician who identified three brothers with low platelet counts, bloody diarrhea, skin rash and recurrent ear infections. All three subsequently died at an early age from complications of bleeding or infection. Notably, their sisters did not have symptoms. Seventeen years later, in 1954, by studying a large six-generation Dutch family with boys who had similar symptoms to the patients described by Wiskott, Dr. Robert Aldrich, an American pediatrician, was able to clarify that the disease was passed down from generation to generation in an X-linked recessive manner.
Whereby the syndrome is named by this two pediatricians.


Jin et al. (2004) employ a numerical grading of severity Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation, 2004

  • 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

Genetic basis

The Wiskott-Aldrich syndrome is an X-chromosome linked recessive disease. It normally affects 1-10 out of 1 million male individuals. The gene associated with this condition is located on the short arm of X chromosome, which is one of the two sex chromosomes. The WASp gene has 12 exons containing 1823 base pairs, coding for a protein called WASP. In the mid-1990s, the disease-causing gene was identified; now, a decade later, more than160 different WAS mutations spanning all 12 exons of the gene have been found in more than 270 unrelated families. Linkage studies have placed the gene at Xp11.22-p11.23.

Here a schematic illustration of WAS representing the 12 exons and the major functional domains.
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation, 2004
A study shows that the most common mutations were missense mutations followed by splice site mutations , deletions, and nonsense mutations. Insertions and complex mutations made up less than 13% of the mutations identified.
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation, 2004
Then they affirm that mutations of the WAS gene result in 3 distinct phenotypes: the classic WAS triad of thrombocytopenia/small platelets, recurrent infections as a result of immunodeficiency, and eczema; the milder XLT variant, characterized predominantly by thrombocytopenia/small platelets and congenital neutropenia without the clinical findings characteristic for WAS/XLT; they then identified 5 mutational “hotspots” in order to make a stronger relation within genotype and phenotype. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation, 2004
Three first mutations found in the study generates simultaneously abnormal and reduced amounts of normal WASP , while the other two normally results in the classical WAS phenotype.
Patients with mutations that allowed the expression of normal-sized mutated protein, often in reduced quantity, developed the XLT phenotype, with a longer life exspentancy, whereas those patients whose lymphocytes could not express WASP or expressed only truncated WASP were more likely to present with the WAS phenotype, with a life exspetancy below 20 years of age.

Because the gene is localized on X gene in females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell may not cause the disorder and women will be carriers. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases of X-linked inheritance, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.


The WAS gene provides instructions for making a protein called WASP. This protein is a 502 aminoacid protein that is restrictively expressed in cells of the hematopoietic system. The Wiskott–Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli and interact with multiple proteins.
There are a number of external signals that trigger global restructuring of the cell through receptors.
All these signals seem to converge on a group of monomeric GTPases within the cell, which are members of the Rho family of proteins: Cdc42, Rho, Rac. Some key targets of Cdc42 are members of the WASp family of proteins.
WASp contains several unique domains including a pleckstrin homology (PH) domain, a guanosine triphosphatase (GTPase) binding domain (GBD), a proline rich region with SH3 binding motifs, and the C-terminal acidic region that is involved in the reorganisation of the actin cytoskeleton by activating Arp2/3 complex- mediated actin polymerization.

In the inactive state, WASP exists in an auto-inhibited conformation with sequences near its C-terminus binding to a region near its N-terminus on is dependent upon Cdc42 and PIP2 acting to disrupt this interaction causing the WASp protein to 'open'. Only costimulation by Cdc42 and phosphatidylinositol (4,5)-bisphosphate PIP2
yields potent polymerization . Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core; this exposes a domain near the WASp C-terminus that binds to and activates Arp2/3 complex, and so enables its interaction with the actin regulatory machinery. Signals acting through other domains of WASp can synergize with CDC42 binding to optimize WASp activity.
Autoinhibition and activation mechanisms of the Wiskott–Aldrich syndrome protein, 2000

The Arp2/3 complex: two of its subunits, the Actin-Related Proteins ARP2 and ARP3 closely resemble the structure of monomeric actin and serve as nucleation sites for new actin filaments. The complex Arp2/3 nucleate the growth of actin filaments from the end negative (-), allowing a rapid elongation end positive (+). The complex can also bind to the sides of existing ("mother") filaments and initiates growth of a new ("daughter") filament at a distinctive 70 degree angle from the mother, thus building, with single strands, a tree-shaped network. Branched actin networks are created as a result of this nucleation of new filaments. The complex Arp is localized in regions of rapid growth of actin filaments, such as lamellipodia. The cytoskeleton is very dynamic and allows the cells to change their shape, to move through specialized structures, such as pseudopodia, form cilia or flagella, strenghtens the plasma membrane, and nuclear transports vesicles in the cytoplasm , allows the movement of certain organelles, constitutes sarcomeres which allow muscle contraction, constitutes the mitotic spindle essential for cell division, supports the dendrites and axons of neurons and interacts with the extracellular environment. It is also responsible of coordination of the shape of the cell, the organization of the mechanical properties from one end, and in the polarization of T-cells during contact with antigen-presenting-cells (APC).

Whereby WASP appears to play critical role in signal transduction and in the cytoskeleton reorganization.

Its mutation is critical, particularly for T and B lymphocytes. Infact, this mutation doesn't permect the correct reorganization of cytoskeleton and that leads to impossibility of B and T lymphocytes to interact, that is basic per B and T activation: its absence impacts the formation of the immunologic synapse, the site of interaction between T cells and antigen presenting cells that depends upon the generation of so-called lipid rafts, which provide a platform to recruit crucial molecules to ensure the stability of the immunologic synapse. Thus, T cell function is defective due to abnormal cytoskeletal reorganization leading to impaired migration, adhesion and insufficient interaction with other cells due to abnormal synapse formation. As a result, WASp deficiency also perturbs B cell homeostasis, resulting in the selective depletion of circulating mature B cells, splenic marginal zone precursors and marginal zone B cells. The phenomenon of lymphocyte numbers declining over time is possibly due to accelerated cell death. WASP is also involved in signal transduction. This lack is correlate with defective Th1 cytokine production .
Furthermore, the wrong organization of the cytoskeleton lead to a decrease of platelets size, fundamental element for a correct diagnosis.
Autoimmunity in Wiskott–Aldrich Syndrome: An Unsolved Enigma, 2012

Signs and symptoms

When a child has WAS, he typically faces:

  • frequent bleeding, even from mild bumps and scrapes, that is hard to slow down or stop
  • eczema (atopic dermatitis) , an inflammatory skin disorder characterized by abnormal patches of red, irritated skin
  • ongoing infections, including pneumonia, ear infections and sinus infections
  • thrombocytopenia and the platelets are usually smaller. Infact instead of from 200,000 to 400,000 platelets per cubic millimeter that are found in the blood of a normal subject, in WAS patients the average is around 15000-35000.

In addition, children with WAS are at elevated risk for developing:

  • other autoimmune diseases
  • anemia
  • arthritis
  • inflammatory bowel disease (IBD)
  • nephritis (kidney inflammation)
  • lymphoma and other malignant cancers

As a matter of fact this mutation of B and T lymphocytes leads to an immunitary deficiency, that is however partiale, in contrast to what happens in SCID (Sever Combined Immunodeficiency Syndrome). Particurarly, WAS patients are able to produce antibodies against certain microorganisms, but not against other germs, like Haemophilus influenzae or pneumococcus. Due to that, infections of this type of bacteria, cannot be normally defeated. Whereby WAS patients develop frequent and recurrent ear infections, pneumonia or even meningitis, or can present like infections in the blood due to both bacteria to fungi(bacteremia, septicemia). Number of T-cells is normal at birth, but progressively decreases in time. Furthermore, T cells present functional defects. For affected males may be encountered little dots of purple on the skin immediately after birth, called petechiae, but the bleeding can be even bigger and look like bruises (purpura), they can also manifest with bleeding gums, prolonged bleeding of the nose, or severe intestinal bleeding (bloody diarrhea). Severe bleeding in the brain may constitute a danger to these children in the past caused the death of about one third of cases. Moreover, because of the increased risk of intracranial bleeding during vaginal delivery, birth by caesarian section may become an option if the diagnosis is known prenatally.

One of the very common problems in older children and in adults with WAS is a high incidence of symptoms of autoimmunity. Infact autoimmune diseases affect from 22% to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy.

Autoimmunity and immunodeficiency: alterations in the cytoskeleton, which already spoken, in patients with WAS, lead to cell biological defect in secretion of granule associated proteins. Whereby the patients present a reduction of secretion of negative immune modulators, such as FasL, and that leads to autoimmunity, or reduction of secretion of effector cytokines, and that leads to immunodeficiency.


Often the WAS is not immediately diagnosed correctly, being confused with other more common causes of thrombocytopenia. The diagnosis is easier when there is a clear family history behind it: because it is a disease transmitted in an X recessive, male patients frequently have
brothers or maternal uncles (mother's brothers) with the same disease. Approximately 60% of cases have a family history of this genre.

  • As already anticipated, the best test to confirm the diagnosis in these patients is a careful determination of the size of the platelets. The most common cause of thrombocytopenia in children, the IdiopathicThrombocytopenic Purpura (PTI) is in fact characterized by platelets that are larger than to the normal ones, while the platelets WAS present approximately half of the normal size (8 instead of 15 u ³ u ³). In neonates, the size of the platelets often constitute the only element to confirm the diagnosis, while in children over two years, the diagnosis is also corroborated by the demonstration of various immunological defects.
  • Another aspect to consider is the number of T-cells: the number of lymphocytes is often normal in children WAS and also stimulation tests of lymphocytes in vitro, using the phytohemagglutinine (a substance of plant origin that makes them multiply), is often normal. Instead, levels of antibodies against blood group antigens (the isoemagglutinine) are low and after vaccination against pneumococcus or Haemophilus influenzae, you do not get the production of specific antibodies.
  • Immunoglobulin levels (IgG, IgM, IgA, IgE): immunoglobulins (antibodies) levels in blood may be low in WAS
  • 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.
  • It is also possible to make a prenatal diagnosis: in the case of a pregnancy of a female carrier of WAS it is possible to carry out, as early as the 12th week, a diagnosis to verify the child's sex, taking of chorionic villi from the maternal womb. If the fetus is male, the tissue samples can be analyzed in the laboratory to verify at the molecular level if he suffers from the syndrome.
  • The search for mutations (genetic errors) in the WASP gene is also important to identify carrier women in families affected by WAS , even before they have children.


There are three main options:

  1. There is the possibility of an allogeneic transplant (bone marrow transplant, BMT): as soon as WAS is diagnosed and its degree of severity found it can be initiated different types of treatment. First of all, if the patient has brothers or sisters ​​healthy it can be made a blood test that determines the degree of compatibility with the patient (the so-called HLA typing). In the positive case, in fact, that of perfect compatibility (HLA-identical), one of the brothers or sisters of the sick child could be used as donor for bone marrow transplantation (BMT).There is another possibility of transplant, which is giving very good results: using the umbilical cord. If a child is waiting for transplant and was born a little sister or a little brother that is compatible, in fact, at the time of birth is taken the umbilical blood, rich of stem cells produced by the bone marrow.
    Phenotypic and Genotypic Correction of WASP Gene Mutation in Wiskott-Aldrich Syndrome by Unrelated Cord Blood Stem Cell Transplantation, 2009
    If there are no compatible donors, however, must be taken into account transplants from partially compatible family donors (as one of two parents, each of which is equal to only 50% to the sick child) or by from the donor bank. In this last case, a search is made continuous national and / or international, through voluntary database that collect information and data about bone marrow donors.
    A bone marrow or cord blood transplant begins with chemotherapy, with or without radiation, to destroy the diseased cells and marrow. The transplant replaces diseased blood-forming cells with healthy ones. The replacement cells are infused into the patient’s blood stream. From there, the cells find their way into the bone marrow, where they start making healthy red blood cells, white blood cells, and platelets.
    Because allogeneic transplant is the only known cure for WAS, it is best to have a transplant as soon as possible. This is because children with WAS are at risk for dying of severe infections before their transplant provides a working immune system. In addition, children who have already had severe infections may be too weak to tolerate a transplant.
    Furthermore, the results of bone marrow transplants with HLA-matched donors in WAS, in fact, are excellent, with a success (final healing of the disease) over 85% of cases.
  2. Splenectomy:
    One option to improve the platelet counts in patients who are not candidates for transplant is splenectomy, a procedure where the spleen is removed. This organ functions as a "filter" for removing old and abnormal red cells and is a storage site for platelets and white blood cells. The spleen also has an important role in the immune system, by filtering and removing foreign molecules and infectious agents, producing antibodies and providing a site for lymphocyte immune function. In WAS patients is thought to remove the spleen and / or entrap abnormal platelets which has an important role in causing the lower platelet counts and their reduced size.
    Patients are hospitalized for a splenectomy and usually you require platelet transfusions prior to surgery to keep the counts over 50,000 / cu.mm. Platelet transfusions usually you are not required after splenectomy.
    Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report, 2011
    Here is a study on splenectomy in the treatment of Wiskott-Aldrich syndrome.
    Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome, 1996
    1. It is estabilished significant improvement in survival in patients who were not transplanted, but underwent splenectomy. Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases, 1993
    2. With improvement in platelet counts, children can lead a life as close to normal as possible, including playing sports and active games (as a matter of fact it reduces the bleeding).
    3. It reduces stress and anxiety for the parents and for the patient.
    4. In patients who have inflammatory diseases (such as arthritis or vasculitis) it improves the quality of life.
    5. In patients undergoing chemotherapy for malignancies the normal platelet counts permits the use of higher doses of chemotherapeutic agents.
    6. This study also indicated that splenectomised patients who are seem to have a shorter duration of illness and the thrombocytopenia easier to manage.
      However it also presents a number of disadvantages, in fact splenectomy is used sparingly by WAS treatment centers, mainly because of the potential post-splenectomy complications, infact it carries significant risk of severe infections and sepsis. However, prolonged survival can be achieved post-splenectomy in patients with WAS, if it is givens systematic approach in their post-splenectomy medical care.
  3. There is also a stem cell gene therapy possible:
    HSC gene therapy has emerged as an innovative therapeutic strategy for various primary immunodeficiency disorders. WAS is a promising candidate disease for gene-therapy approaches, since WASP expression is restricted to cells of the hematopoietic system, which grants a proliferative advantage over WASP-negative cells. After gene therapy the percentage of WASP-expressing B cells, WASP-expressing monocytes, WASP-positive NK cells increased over time and abnormal immunoglobulin levels normalize; the fraction of podosome-positive monocytes after gene transfer increased, indicating that restored WASP expression reconstituted the capacity to rearrange the cytoskeleton in myeloid cells and T-cell proliferative responses were reconstituted at multiple time points in patients.
    Furthermore an increase in platelet counts was noted, starting 6 to 9 months after gene therapy, which marked the reduction of frequency and severity of infections decreas, as well as signs and symptoms of autoimmunity.
    Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome, 2010
    In a recent clinical trial, a γ-retroviral vector was used to introduce a functional WAS gene into autologous hematopoietic stem/progenitor cells (HSCs), followed by reinfusion of the gene-corrected HSCs into the patients. This strategy provided clinical benefit, with improving platelet counts, protection from bleeding and severe infections, and resolution of eczema, but resulted in expansion and malignant transformation of hematopoietic clones carrying vector insertions near oncogenes, thus increasing leukemia risk.
    Development of lentiviral gene therapy for Wiskott Aldrich syndrome, 2008

Here's a comparison between the three methods.
Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation, 2007

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