Wiskott-Aldrich syndrome

Rare disease with eczema, bleeding diathesis and recurrent infections in boys.

X-linked recessive disorder.

Complex primary immunodeficiency disorder with recurrent infections, thrombocytopenia, eczema, and autoimmunity.

Estimated incidence 1:100,000 births.

Caused by loss of function mutations in WAS (D2242y JM et al).

WAS protein is a key regulator of actin polymerization in hematopoetic cells, with domains affecting signaling, cell locomotion and immunologic-synapse formation (Thrasher AJ).

WAS protein a key regulator of the actin cytoskeleton in all hematopoietic lineages.

Boys with Wiskot-Aldrich syndrome have frequent ear infections, eczema, and platelet deficiency and are found to have an atrophic thymus, severe lymphocyte deficiency, inability to survive herpes simplex virus infections and yet have abundance of plasma cells in and their immunoglobulin products.

WAS protein deficiency causes micro thrombocytopenia and lymphoid and myeloid cell dysfunction, the severity of which correlates with WAS protein expression levels.

Typically children present with petechiae, bruising and bloody diarrhea shortly after birth.

Phenotype characterized by bleeding diathesis, susceptibility to opportunistic infections, persistent eczema, autoimmune diseases, inflammatory complications, and elevated risk of lymphomas.

Bleeding associated with thrombocytopenia and small platelets.

Prolonged bleeding following circumcision can lead to the finding of thrombocytopenia.

Multiple dysfunctions in T and B cells, impaired NK-cell immunologic synapse, the effective migratory responses in all leukocyte subgroups.

Defective lymphocyte function associated with recurrent infections, autoimmune manifestations and increased incidence of lymphoma later in life.

Classic presentation as early as the neonatal period of bruising, petechiae, bloody diarrhea, purulent otitis, pulmonary infections and eczema.

Mean platelet volume 3.8-5 fL compared to 7-10.5 fL in healthy subjects.

Platelet morphology changes are seen in the Wiskott-Aldrich syndrome with the smallest platelets being present.

Classic presentation as early as the neonatal period of bruising, petechiae, bloody diarrhea, purulent otitis, pulmonary infections and eczema.

Patients have cellular and humoral immunodeficiency with associated recurrent bacterial, viral and fungal infections.

Severe disease leads to early death from infection or bleeding.

Thrombocytopenia involves decreased production of platelets and increased platelet destruction by immune and non-immune mechanisms.

Stem cell gene therapy may be efficacious (Boztug K et al).

In the absence of treatment patients do not survive Into second and third decade of life.

Presently only curative therapy is a allogeneic hematopoetic stem cell transplant.

Gene therapy with Moloney leukemia virus gamma retro viral vector provided benefit with partial or complete resolution of immunodeficiency, autoimmunity and blleeding risk, but was associated with insertional mutagenesis leading to leukemia.

Gene therapy with lentiviral vector has demonstrated efficacy without toxicity.

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