Etiology

The condition is caused by mutations in the WAS gene, located on the X-chromosome (Xp11.23-p11.22).[10][11][12] If the mother is a carrier of a WAS mutation, the chance of transmitting the mutation is 50% in each pregnancy; males who inherit the mutation will be affected, while females who inherit the mutation will be carriers; all males with the mutation will pass it on to all of their daughters and none of their sons.

Approximately 300 unique mutations have been reported, affecting all 12 exons of the WAS gene.[12] These mutations all result in loss of function through reduced gene expression and/or reduced WAS protein (WASp) expression in hematopoietic cells. In general, mutations resulting in absence of protein lead to severe clinical disease while mutations preserving some, albeit reduced, WASp expression are associated with attenuated WAS (X-linked thrombocytopenia).[13] While this division is clinically useful, it is not absolute as some patients with residual protein may still develop severe manifestations, presumably related in part to the functionality of the residual protein, but also to secondary genetic influences and variable environmental factors.

Pathophysiology

WAS protein (WASp) is normally expressed only in hematopoietic cells, and therefore defects in WAS are confined to blood cell lineages. WASp has a key role in transducing signals from the cell membrane to regulate the actin cytoskeleton. In the absence of WASp (classical WAS), cytoskeletal rearrangement is defective and certain actin structures, such as phagocytic cups and contacts for adhesion, are not formed normally. This disrupts diverse white blood cell functions, including phagocytosis, migration, and intercellular interactions, resulting in immunodeficiency. Although there are few studies of cell function in patients with residual low levels of WASp (attenuated WAS), this group likely retains more normal immune cell function.

The pathophysiology of platelet dysfunction in WAS is not well understood; it seems to relate both to increased splenic clearance of platelets with abnormal structure and to defective megakaryocyte function.[14] Unlike immunodeficiency, significant thrombocytopenia and a bleeding tendency is seen regardless of whether WASp expression is reduced or absent.

The underlying mechanisms for eczema and autoimmunity are also poorly understood. There is good evidence for defective T-regulatory function in WAS, but other aspects of autoimmunity have been poorly studied.[15][16] Similarly, the pathogenesis of malignancy in WAS is not clear. Immunodeficiency may play a role, as a significant proportion of WAS malignancies are Epstein–Barr virus-driven.[14]

Use of this content is subject to our disclaimer