Clinical Description
Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN) are a spectrum of disorders caused by WAS pathogenic variants that result in deficiency of the Wiskott-Aldrich syndrome protein (WASP), leading to low platelet counts (with small platelet size) and significant risk of serious bleeding, and, in some individuals, abnormal lymphocyte function with susceptibility to serious bacterial, viral, and fungal infections. Autoimmune disorders and lymphomas are frequently encountered in individuals with pathogenic variants in WAS.
Attempts have been made to classify affected individuals as having either XLT or Wiskott-Aldrich syndrome based on (1) presence or absence of autoimmune or inflammatory complications, (2) presence or absence of WASP, (3) the WAS clinical score (see following), or (4) type of WAS pathogenic variant; however, it has not been possible to eliminate the considerable overlap between XLT and Wiskott-Aldrich syndrome, an observation that emphasizes the notion that the phenotypes comprising the WAS-related disorders comprise a spectrum, not discrete entities. WAS-related disorders usually present in infancy; however, because the clinical phenotype may worsen with age, it is particularly difficult to predict eventual disease severity in an infant. The range of clinical complications experienced by affected males can vary widely, even in the same kindred. Long-term prognosis varies based on the predicted disease burden in a particular individual. In some families, adult males in their 60s have mild manifestations such as chronic thrombocytopenia, whereas other affected male relatives succumb from complications of severe manifestations in infancy and childhood [Beel & Vandenberghe 2009, Albert et al 2011, Buchbinder et al 2011].
The prognosis for individuals with WAS-related disorders has improved in the last 20 years as a result of improved treatment (see Management).
The WAS clinical score is derived from a variety of clinical parameters, including the presence of thrombocytopenia, eczema, immunodeficiency, autoimmunity, and malignancy. WAS scores, which range between 0 and 5, facilitate the clinical categorization of individuals and may be useful in predicting disease severity [Albert et al 2011]. A WAS score of 0 is reserved for those individuals with XLN and/or myelodysplasia. A score of 1 or 2 defines individuals with XLT; a score of 3 to 4 identifies individuals with classic WAS; and a score of 5 is reserved for individuals with either XLT or WAS who develop autoimmunity and/or malignancies. Individuals with a higher WAS score (e.g., 5) at a younger age (e.g., during the first 2 years of life) may represent a group at high risk for morbidity and mortality [Mahlaoui et al 2013]. As progression of the disease can occur at a later age, individuals may transition from a lower to a higher WAS score (e.g., some individuals originally diagnosed with XLT [score of 1 to 2] may develop autoimmunity or cancer later in life [score of 5]) [Albert et al 2010].
Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome usually presents in infancy. Although a triad of (1) bloody diarrhea, mucosal bleeding and/or petechiae; (2) eczema; and (3) recurrent middle-ear infections and purulent drainage from the ears was originally described [Aldrich et al 1954], this triad is identified in only 27% of children with Wiskott-Aldrich syndrome [Sullivan et al 1994].
Common manifestations of Wiskott-Aldrich syndrome include the following.
Thrombocytopenia is usually present at birth; however, near-normal platelet counts in the newborn period, followed by chronic thrombocytopenia, have been reported. Intracranial bleeding is a potential early life-threatening complication. Intermittent mucosal bleeding and bloody diarrhea are commonly observed, as are intermittent or chronic petechiae and purpura. Life-threatening bleeding occurs in 30% of males prior to diagnosis and accounts for 23% of all non-hematopoietic cell transplantation (HCT)-related deaths [Sullivan et al 1994]. Platelet counts do not adequately represent bleeding risk in an individual with Wiskott-Aldrich syndrome [Albert et al 2010].
Thrombocytopenia may be reversed by splenectomy; however, recurrent thrombocytopenia associated with the development of immune thrombocytopenia purpura (ITP) is observed in some splenectomized individuals.
Eczema occurs in about 80% of males with Wiskott-Aldrich syndrome [Sullivan et al 1994]. The severity varies from mild to severe and tends to be worse in males with a family history of allergies and asthma.
Other skin disorders including impetigo, cellulitis, and abscesses are common.
Infection. Boys with Wiskott-Aldrich syndrome are susceptible to recurrent bacterial and viral infections, particularly recurrent ear infections. They have an increased risk of mortality secondary to bacterial sepsis from encapsulated organisms including Streptococcus pneumonia and Haemophilus influenza B.
Infections by opportunistic agents including cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), and adenovirus are common. Pneumocystis jiroveci pneumonia (formerly known as Pneumocystis carinii pneumonia, or PCP) is a possible early life-threatening complication.
Splenectomy, commonly performed in the past to increase platelet counts and reduce risk of fatal hemorrhage, increases the risk of overwhelming bacterial infection.
Autoimmune disorders. The risk of developing an autoimmune disorder increases with age. Roughly 25%-40% of males who survive the early complications of Wiskott-Aldrich syndrome develop one or more autoimmune conditions including hemolytic anemia (destruction of red blood cells), immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis of small and large vessels, and immune-mediated damage to the kidneys and liver [Sullivan et al 1994, Chen et al 2015]. For a comprehensive review of autoimmunity in Wiskott-Aldrich syndrome, see Schurman & Candotti [2003] and Catucci et al [2012].
High serum IgM concentration in young children prior to splenectomy may be a risk factor for the development of autoimmune hemolytic anemia [Dupuis-Girod et al 2003]; however, the predictive value of this finding awaits confirmation by other investigators.
The presence of an autoimmune disorder significantly increases the risk of developing lymphoma [Sullivan et al 1994, Schurman & Candotti 2003].
Allogeneic HCT corrects autoimmunity in individuals with Wiskott-Aldrich syndrome [Pai et al 2006].
Lymphoma. Individuals with Wiskott-Aldrich syndrome, particularly those who have been exposed to Epstein-Barr virus (EBV), have a high risk of developing lymphomas, which often occur in unusual, extranodal locations such as the brain, lung, or gastrointestinal tract. Although B-cell lymphomas predominate, EBV-associated T-cell lymphomas and Hodgkin lymphomas have also been reported.
Approximately 13% of individuals with Wiskott-Aldrich syndrome develop lymphoma, at an average age of 9.5 years. The risk of developing lymphoma increases with age and in the presence of autoimmune disease [Schurman & Candotti 2003].
The prognosis of individuals with Wiskott-Aldrich syndrome following conventional chemotherapy is poorer than that of age-matched normal controls. Individuals with Wiskott-Aldrich syndrome have a significant risk of relapse or development of a second de novo lymphoma. Individuals with Wiskott-Aldrich syndrome and lymphoma should undergo allogeneic HCT to increase their chances of relapse-free survival.
Life span. The reported median survival of children with Wiskott-Aldrich syndrome who do not undergo successful allogeneic HCT is between eight and 14.5 years [Dupuis-Girod et al 2003]. The causes of non-HCT-related deaths include infection (44% of individuals), malignancy (26%), and bleeding (23%). Survival into adulthood occurs, particularly given the improvement in medical treatment of this disorder over the last 20 years. HCT provides a potential cure for Wiskott-Aldrich syndrome [Friedrich et al 2009].
X-Linked Thrombocytopenia (XLT)
Males with XLT have small platelet volume and thrombocytopenia that may be intermittent. Albert et al [2010] found that life expectancy was not significantly affected in males with XLT as a group; however, severe disease-related events including life-threatening infections, bleeding, autoimmune diseases, and malignancies were common.
X-Linked Neutropenia (XLN)
Males with XLN typically present with congenital neutropenia associated with myelodysplasia, increased myeloid cell apoptosis, and lymphoid cell abnormalities. Beel & Vandenberghe [2009] described two males with XLN who developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Boztug & Klein [2011] estimate that 20%-30% of males with XLN are at risk for MDS or AML.
Genotype-Phenotype Correlations
Individuals with Wiskott-Aldrich syndrome show remarkable variable expressivity of clinical findings.
While several reports described missense variants in association with XLT or mild disease and nonsense, frameshift, or splice site variants in severe disease [Zhu et al 1997, Notarangelo & Ochs 2003, Imai et al 2004, Liu et al 2015], other studies failed to find consistent correlation between a particular pathogenic variant and clinical outcome [Greer et al 1996, Schindelhauer et al 1996, Lemahieu et al 1999, Fillat et al 2001].
XLT is typically associated with WAS pathogenic missense variants and most males with XLT are able to produce WASP. Specific pathogenic variants are not universally associated with XLT and disease severity varies considerably within families [Albert et al 2011, Liu et al 2015].
XLN is caused by rare pathogenic variants in WAS, generally described in the GTPase binding domain, which cause constitutive activation of WASP and lead to increased formation of actin polymers and abnormal cell division. WASP expression in individuals with XLN is comparable to that of normal controls [Devriendt et al 2001]. Disease severity varies considerably within families [Beel & Vandenberghe 2009].
While predictions can sometimes be made based on groups of affected individuals or types of pathogenic variant, considerable caution must be exercised in assigning a phenotype to a young, newly diagnosed male based on genotype alone for the following reasons:
Splice site variants may allow production of multiple
gene products, including normally spliced WASP [
Jin et al 2004].
It is likely that the clinical
phenotype in
WAS-related disorders, as in many other monogenic disorders, is modified by other genes (e.g., those modifying atopy) and results, in part, from encounters with ubiquitous or rare pathogens.
Some studies have focused on WASP expression as a better predictor of clinical severity of a WAS-related disorder than the pathogenic variant alone.
In one study, 74.2% of individuals who produced WASP had the XLT
phenotype, while 86.5% of individuals who produced no WASP had the Wiskott-Aldrich syndrome phenotype [
Imai et al 2003]. Similarly,
Liu et al [2015] demonstrated that 75% of individuals diagnosed with XLT had detectable WASP while the majority of individuals with classic Wiskott-Aldrich syndrome did not express WASP in peripheral blood mononuclear cells.
As a group, individuals who expressed normal-sized mutated WASP were significantly less likely to develop autoimmune disease and/or malignancy than individuals who did not express WASP or who expressed only a truncated protein [
Jin et al 2004].
Lutskiy et al [2005] proposed that clinical
phenotype was dependent on the presence or absence of WASP, the level of protein expression, and the molecular structure of the protein; they documented good clinical correlation for five of the most common pathogenic variants in
WAS.