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.
Further readings
Wiskott-Aldrich Syndrome