Continuing Education Activity

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder which classically includes the characteristic triad of immunodeficiency, thrombocytopenia, and eczema. It results from a genetic mutation in the gene encoding Wiskott-Aldrich syndrome protein (WASp). The disease has variable presentation ranging from the severe phenotype (classic WAS) to milder ones (X-linked thrombocytopenia and X-linked neutropenia). This activity describes the pathophysiology, etiology, presentation, and evaluation of Wiskott-Aldrich syndrome, and highlights the role of the interprofessional team in the management of affected patients.

Objectives:

• Describe the etiology of Wiskott-Aldrich syndrome.
• Review the pathophysiology of Wiskott-Aldrich syndrome.
• Summarize the treatment options for Wiskott-Aldrich syndrome.
• Explain the importance of improving care coordination among interprofessional team members to enhance outcomes for patients affected by Wiskott-Aldrich syndrome.

Introduction

Wiskott-Aldrich syndrome is a rare X-linked disorder with a characteristic triad of immunodeficiency, thrombocytopenia, and eczema. It results from a genetic mutation in the gene encoding Wiskott-Aldrich syndrome protein (WASp) affecting the immune system and inducing a state of immunodeficiency. The disease follows a broad spectrum depending on gene mutations ranging from severe phenotype (classic WAS) to milder ones (X-linked thrombocytopenia (XLT) and X-linked neutropenia).

Etiology

The etiology of Wiskott-Aldrich syndrome is mutations in the WAS gene responsible for the production of WAS protein involved in cellular signaling and immunological synapse formation. These mutations alter the protein configuration in several ways leading to phenotypic variability in disease manifestations.

Epidemiology

This X-linked disorder demonstrates an estimated incidence of 1 in every 100000 live births. It is seen almost exclusively in males.[1] There is no ethnic or geographical predominance.  The condition may be under-reported because of misdiagnosing of mild cases as idiopathic thrombocytopenia purpura.

Pathophysiology

Wiskott-Aldrich syndrome is the result of an X-linked genetic defect in the WAS gene located on short arm of the X-chromosome at Xp 11.22-23 position. The gene product Wiskott-Aldrich protein (WASp) is a 502 amino acid protein expressed in the cytoplasm of non-erythroid hematopoietic cells.  More than 300 gene mutations have been identified leading to impaired protein configuration. The most common mutations are missense mutations followed by non-sense, splice site and short deletion mutations. Because of the wide range of genetic mutations, the disease itself has phenotypic variability ranging from severe (classic WAS) to mild disease X linked thrombocytopenia and X linked neutropenia.

As mentioned earlier, the WAS protein expresses in non-erythroid hematopoietic cells where it functions as a bridge between signaling and movement of actin filaments in the cytoskeleton. This ultrastructural component of the cellular architecture is primarily responsible for intracellular and cell-substrate interactions and signaling because of its role in cell morphology and movements.[2] The actin cytoskeleton is involved in various cellular functions such as growth, cytokinesis, endocytosis, and exocytosis. It also has involvement in the formation of an immunologic synapse, which is the site of interaction between T cells and antigen-presenting cells like dendritic cells. The interaction depends on the generation of lipid rafts, which provide a platform to recruit crucial molecules to ensure the stability of immunologic synapse.[3][4] In Wiskott-Aldrich syndrome, there is abnormal cytoskeleton reorganization because of impaired gene expression leading to T cell dysfunction causing impaired migration, adhesion and insufficient interaction with other cells due to abnormal synapse formation; this affects B cells homeostasis resulting in selective depletion of circulating mature B cells splenic marginal zone precursors, and marginal zone B cells.  This event of lymphocyte numbers declining over time is due to accelerated cell death.[5] Circulating natural killer cells are normal or increased, but cytotoxicity of these WAS protein deficient cells is impeded as a result of impaired immunologic synapse formation. Interleukin-2 can help to restore cytotoxicity in natural killer (NK) cells by inducing the expression of a functionally related protein. Invariant natural killer T cells are completely absent in patients with WAS and X linked thrombocytopenia, which predisposes patients to increased risks for autoimmunity and cancer.[6] Mechanisms of autoimmunity in WAS include inadequate Treg cell function, B cell-intrinsic loss of tolerance via positive selection of self-reactive transitional B cells, expansion of autoreactive B cells and production of autoantibodies, impaired Fas-mediated apoptosis of self-reactive lymphocytes, and defective phagocytosis of apoptotic cells resulting in chronic inflammation.[7]

WASp-deficient myeloid lineage cells exhibit impaired phagocytosis and chemotaxis. Also, monocytes, macrophages, and dendritic cells from WASp-deficient patients demonstrate almost completely abrogated assembly of actin-rich structures responsible for cellular migration leading to impaired chemotaxis to specific chemoattractants.[8][9] The explanation for thrombocytopenia is increased clearance, ineffective thrombocytopoiesis, reduced platelet survival due to intrinsic platelet abnormalities, and immune-mediated events.

Whereas "loss-of-function" mutations in the WAS gene cause either XLT or WAS, unique "gain-of-function" missense mutations impair the autoinhibitory conformation of the molecule and lead to increased actin polymerization, resulting in congenital neutropenia.

History and Physical

The disease manifests as follows:

Bleeding:  Thrombocytopenia is present at birth. It is the most common finding present at the time of diagnosis. Affected patients may present in the first days of life with petechiae and prolonged bleeding from the umbilical stump or after circumcision. Other manifestations may include purpura, hematemesis, melena, epistaxis, hematuria, and such life-threatening symptoms as oral, gastrointestinal, and intracranial bleeding. A subset of infants less than or equal to 2 years of age may present with "severe refractory thrombocytopenia," possibly due to antiplatelet autoantibody, a complication that is associated with poor prognosis.[10]

Immunodeficiency:  The severity of immunodeficiency depends largely on the type of mutations and resulting protein expression. Patients usually present with multiple recurrent infections and failure to thrive. Patients are susceptible to encapsulated organisms as Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae. Manifestations include otitis media, sinusitis, pneumonia, meningitis, sepsis, and colitis. Splenectomy, which is occasionally performed to decrease the risk of bleeding, further increases the risk of severe infections and sepsis. This immunodeficiency also predisposes patients to opportunistic infections with Pneumocystis jirovecii, Molluscum contagiosum, as well as systemic varicella and cytomegalovirus infection. Fungal infections are relatively rare consisting primarily of mucocutaneous infection due to Candida albicans.

Eczema:  Eczema of varying severity develops in approximately one-half of WAS patients during the first year of life and resembles classical atopic dermatitis.

Autoimmune manifestations:  Reports exist of autoimmune diseases include hemolytic anemia, neutropenia, vasculitis involving both small and large vessels, inflammatory bowel disease, and renal diseases. A broad spectrum of autoantibodies has been observed both in classic WAS and in XLT.

Malignancies:  Malignancies can occur during childhood but are most frequently present in adolescent and young adult males with the classic WAS phenotype. B cell lymphoma (often Epstein-Barr virus-positive) and leukemia are common in classic WAS but do occur in XLT.

The disease has three main clinical phenotypic manifestations:

Classic (severe) Wiskott-Aldrich syndrome:  This is the severe phenotype of WAS. Affected boys present in early childhood with a hemorrhagic diathesis due to thrombocytopenia; recurrent bacterial, viral and fungal infections; and extensive eczema. Lymphadenopathy is frequently present, especially in those WAS patients with chronic eczema, and hepatosplenomegaly is common. Patients with classic WAS tend to develop autoimmune disorders and lymphoma or other malignancies, often leading to early death.[11]

X-linked neutropenia (XLN):  XLN presents mainly as congenital neutropenia. Patients with XLN present with infections characteristic for neutropenia but may also develop infections associated with lymphocyte dysfunction. These patients also have an elevated risk for myelodysplasia.[12]

 X-linked thrombocytopenia (XLT):  XLT presents as congenital thrombocytopenia that is sometimes intermittent (IXLT).[13] Eczema is usually mild. These patients generally have a benign disease course and good long-term survival. They still carry an increased risk (lower than that for WAS) for severe events such as life-threatening infections (especially post-splenectomy), serious hemorrhage, autoimmune complications, and cancer.[14] Any male with thrombocytopenia and small platelets should be evaluated for WASp expression and WAS gene mutations.

Evaluation

A diagnosis of Wiskott-Aldrich syndrome or X-linked thrombocytopenia (XLT) is a consideration in any male patient who presents with petechiae, bruises, and congenital or early-onset thrombocytopenia associated with small platelet size. For diagnostic confirmation, a deleterious mutation in the WAS gene is necessary. Presence of mild or severe eczema supports the diagnosis. Infections and immunologic abnormalities may be absent, mild, or severe. Autoimmune diseases and malignancies develop more often in patients with classic WAS than in those with XLT. Screening for presence or absence of WAS protein (WASp) can be performed in lymphocytes by flow cytometry using an anti-WASp antibody.[15] The diagnosis of XLN should be considered in any male patient presenting with severe congenital neutropenia.

Immunology:  Abnormal immunologic findings in patients with WAS include decrease number and function of T cells and regulatory T cells, abnormal immunoglobulin (Ig) isotypes, defective antigen-antibody response, impaired cytotoxicity of natural killer cells with normal to increased cell numbers, impaired chemotaxis of neutrophils and phagocytic cells. Absolute lymphocyte counts are usually normal during infancy, but T and B cell numbers decrease later in life in patients with classic WAS. Reported variations in the levels of Ig including normal levels of serum IgG, decreased levels of IgM, and elevated levels of IgA and IgE also exist.

Histopathology:  Abnormal findings in lymphoreticular tissue are commonly present, including varying degrees of T cell zone depletion in lymph nodes and spleen, decreased number of follicles and abnormal follicular formation devoid of marginal zone, and regressive or "burned out" germinal centers.[16]

Thrombocytopenia and platelet abnormalities:  Thrombocytopenia associated with small platelet volume is a consistent finding in patients with WAS gene mutations, except for those presenting with an XLN phenotype. Platelet counts are generally 20000 to 50000 per mm but may drop below 10000 per mm.

Treatment / Management

The management of Wiskott-Aldrich syndrome mainly depends on the conventional and supportive care which includes broad-spectrum antibiotics for bacterial infections, antivirals/antifungals for viral and fungal infections respectively. Patients also require platelet transfusions to prevent bleeding. Topical steroids are used to treat eczema. A discussion of further treatment falls under the following subheads:

Intravenous immune globulin therapy:  Intravenous immunoglobin (IVIG) therapy is indicated in WAS and XLT patients with significant antibody deficiency. The dose is usually higher than that used for other primary immunodeficiencies due to an increased catabolic rate observed in WAS patients. Immune globulin may also be given subcutaneously. This route of administration requires caution in this patient population because of the bleeding tendency.[17]

Eltrombopag:  An oral thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia (ITP), may be useful in preventing bleeding in patients with WAS who are awaiting hematopoietic cell transplantation (HCT).[18]

Immunosuppressive treatment:   Immunosuppressive treatment may be necessary for autoimmune manifestations. Autoimmune cytopenias often respond to the monoclonal antibody rituximab which is relatively safe for those patients already receiving therapy with IVIG.

Splenectomy:  Elective splenectomy has been advocated in selected patients to reverse the thrombocytopenia and arrest the bleeding tendency by increasing the number of circulating platelets. Patients who undergo splenectomy require lifelong antibiotic prophylaxis and are at increased risk of septicemia.

Hematopoietic cell transplantation:  HCT is the only available curative treatment, with excellent results for patients with human leukocyte antigen (HLA)-matched family or unrelated donors (URDs) or partially matched cord-blood donors.

Gene therapy:  Gene therapy is an alternative, potentially curative therapy under investigation for WAS.

Differential Diagnosis

Several syndromes presenting with eczema, elevated serum immunoglobulin E (IgE), and susceptibility to infections may resemble WAS/X-linked thrombocytopenia (XLT) including:

• Hyper Ig syndrome
• Omenn syndrome
• Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)
• Atopic dermatitis
• Immune thrombocytopenic purpura
• Congenital neutropenia

Prognosis

The prognosis of X-linked thrombocytopenia is good with the life expectancy as close to the normal population,[14] but classic Wiskott-Aldrich syndrome has a poor prognosis with decreased life expectancy due to recurrent infections, autoimmune disease, and malignancy. Bleeding is most frequently the cause of death in these patients.[11]

Enhancing Healthcare Team Outcomes

Because Wiskott-Aldrich syndrome is a rare X-linked disorder seen in males, its management is best with an interprofessional team approach including consultation with hematology, dermatology, pathology, infectious disease expert, geneticist, nursing staff, and pharmacist. The diagnosis is made by clinical/laboratory findings and genetic testing. Disease treatment is by conventional and supportive care including the use of prophylactic antibiotics and platelet transfusions to stop life-threatening hemorrhages. Intravenous immunoglobulin therapy is indicated in patients with antibody deficiency. Hematopoietic stem cell transplantation is the only curative treatment available.