was

Wiskott-Aldrich Syndrome

Introduction

Wiskott-Aldrich Syndrome (WAS) is a very rare X linked primary immunodeficiency disorder with bleeding tendency. Patients are susceptible to bacterial and fungal infections. It is usually diagnosed in boys at 1-2 years. The problems with easy bruising and bleeding in patients with WAS result from having low counts of small, non-functional platelets. Frequent infection is because of defective T cell function. Prevalence is 1 in 10 million boys.

Pathology

X linked recessive disorder. Seen in boys since X linked and girls are carriers. Abnormalities in immune system function (cell- mediated, humoral, and innate immunity) in WAS results in susceptibility to a wide variety of infectious pathogens.

The patients have immunological abnormalities particularly of T lymphocytes both quantitatively and qualitatively. They also have low numbers of circulating lymphocytes due to increased apoptosis and show striking depletion of the thymus-dependent portions of the peripheral lymphoid tissues. T-cell chemotaxis, activation, and cytokine secretion are also impaired in patients with WAS. The germinal centre and plasma cell development is normal. Impaired T-cell function may impair the maturation and differentiation of B cells into antibody producing cells and memory cells. However, intrinsic defects in B cells are also notable in patients with WAS. Immunoglobulin levels are thus low.

The genetic defect in primary inability to process certain polysaccharide antigens is responsible for all the defects. WAS patients respond to certain antigens with normal IgM and IgG antibody synthesis. However the ability to form antibodies to several polysaccharide antigens, including blood groups A and B and Forssman antigens, is deficient. Nonspecific defense mechanisms were found to be normal.

Platelets with abnormal function is responsible for the bleeding episode in patients. The defects in platelet production and function relate to the role WAS protein plays in the process of platelet formation, activation, and associated cytoskeletal remodeling.

Autoimmunity in WAS may be due to the formation of autoantibodies or the presence of autoreactive T-cell clones. Lymphomas, mainly non Hodgkin's lymphomas, are common.

Genetics

Defective gene is the one that is responsible for WAS protein (WASP) located in the short arm of the X chromosome at Xp11.22–p11.23. WASP is necessary for the cytoskeletal organization of blood cells. WASF2 is the gene that codes for multiprotein complex (WAS protein) that links receptor kinases and actins. The signalling of this causes change in shape, size and motility of the cells. Defective gene shows following abnormalities:

1. Paucity of microvillus on surface of T cells (because of defective cytoskeleton organization).

2. Abnormalities in the glycosylation of the cell surface.

3. Defective signalling.

4. Loss of T cell proliferation to antigenic stimulation.

WASP gene is seen in spleen, thymus and lymphocytes. Cluster of differentiation 43 (CD43) or sialophorin absence is also linked to WAS. CD43 expressed in monocytes and lymphocytes are responsible for intracellular signalling and activation of the cell.

Clinical features

There is a triad of clinical features in WAS

1. Eczema,

2. Severe thrombocytopenia and microthrombi causing easy bruising, bloody diarrhoea etc.

3. Profound immunodeficiency, neutropenia, decrease B and T lymphocytes. This increases the susceptibility to infection of which sinopulmonary infections is the most common. Infection of Pneumocystis jirovecii is common.

Other clinical features are,

Autoimmune diseases like haemolytic anaemia, vaculitis are seen.

Delayed hypersensitivity response is impaired in WAS. Autoimmune diseases are also seen.

Later lymphoreticular malignancies and leukemias are common.

The patient may die of infections or because of uncontrolled blood loss.

Without treatment the life expectancy is about 8 years.

Diagnosis

Presentation: Children 1-2 years present with easy bruising, bleeding tendencies, decreased platelet counts. Bacterial infection is also seen. There are 4 types:

a. Classic WAS

b. X linked thrombocytopenia

c. Intermittent thrombocytopenia

d. X linked neuropenia

Of all the 4 types 1st one is the most severe form of WAS.

Lab diagnosis:

1. Complete blood count

2. Immunoglobulin levels

3. Specific antibody titres

4. Genetic testing.

5. WASP levels in WBCs.

Prophylaxis and treatment

i. Antibiotics, antivirals, antifungal drugs to prevent infections. Immunization is compulsory.

ii. Reducing risk of head injury to prevent intracranial hemorrhage.

iii. NSAIDs use must be controlled as they further impair platelet function.

iv. Hematopoietic stem cell transplant. Immunosuppression and complete bone marrow irradiation is needed as the patient can to some extent have CMI (cell mediated immunity). Measures to prevent graft versus host reaction should be taken.

v. Gene therapy: γ- retrovirus is used as the vector and WASP gene is transferred into hematopoietic stem cell. Since retroviruses integrate with human DNA it has its own side effects. They can cause leukemias, unwanted immune response, infections caused because of the virulence of the vector virus used.

vi. Acute loss of blood should be controlled as it leads to hypovolemic shock and death.

vii. Intravenous immunoglobulin G is given in severe cases like in classic WAS as prophylaxis.

viii. Moisturizers and steroids for eczema.