**4.3 Immunodeficiency**

Abnormalities in immune system function (i.e., cell-mediated, humoral, and innate immunity) among patients with WAS give rise to vulnerability to a wide range of infections pathogens. Nevertheless, infectious complications as a primary manifestation are not frequent (<5% of cases). Opportunistic infections such as molluscum contagiosum infections, extensive candidiasis, aspergillosis, and

*Pneumocystis jirovecii* may also present in WAS patients [5, 9, 10]. Patients with WAS can suffer from severe and disseminated forms of herpes simplex virus I or II (6% of cases) and varicella (3% of cases) as the most widespread pathogens. In 10% of cases, Invasive yeast and fungal infections have been reported. Generally, Sinopulmonary infections are classified as the most common infectious manifestation before diagnosis, including otitis media (64% of cases) and pneumonia. Other severe infectious complications are less likely to occur, such as sepsis (7% of cases) and meningitis (4% of cases) [6]. However, Viral infections caused by pathogens such as EBV, CMV, and HPV can be extremely severe.

In WAS patients, both quantitative and qualitative defects in T cells are manifested T cell lymphopenia as a common disorder is seen more in naive T lymphocytes than in memory cells and CD8. This event may result from increased apoptosis and can appear from early life and subsequently affect thymic output [11, 12]. More often than not, WAS patients have got an absolute lymphocyte count >1,000/μL, demonstrating the lack of the profound lymphopenia seen in other primary immunodeficiency disorders. Of note, an absolute lymphocyte count of <1,000/μL was presented in only 22% of cases. Processes such as T-cell activation, chemotaxis, and cytokine secretion are disturbed in patients with WAS [13, 14].

Humoral immunodeficiency is another characteristic of WAS patients. High serum levels of IgE and Low levels of IgM, IgG, and IgA are observed [5]. Abnormal isohemagglutinin titers (84% of cases) and insufficient vaccine responses to protein (e.g., 62% with abnormal responses to tetanus vaccine), polysaccharide (e.g., 69% with abnormal responses to the pneumococcal vaccine), and conjugate vaccines (e.g., 66% with abnormal responses to Hib (*Haemophilus influenzae* type b) conjugate vaccines, implies that antibody responses may be abnormal [5]. Malfunctions in T-cell mentioned earlier may disturb the maturation and differentiation of B cells into antibody-producing cells and memory cells [15].

Perturbations in the components of the innate immune response may also be present. The number of Natural Killer (NK) cells can be in the normal range or increase. Nonetheless, most of the time, NK cell function is abnormal, including Immunological synapse formation, stimulation of secretory granules, and consequent cytolytic activity [16]. Despite the normal numbers of neutrophils, monocytes, and other phagocytes, functional abnormalities may be present in WAS patients. Chemotaxis, adhesion/arrest function, DC motility, the initiation of degranulation, the formation of a functional respiratory burst, and antibodymediated phagocytosis are more likely to be impaired [17, 18].

#### **4.4 Eczema**

Eczema is one of the specific findings that essentially leads to the differentiation of WAS from ITP. Skin manifestations resemble acute or chronic eczema in appearance and distribution. Eczema of varying severity occurs in approximately 50% of WAS patients during the first year of life and resembles classic atopic dermatitis. [2]. According to a large cohort study, 81% of WAS patients are classified into mild or severe, transient, or consistent, depending on their eczema history. In severe form, eczema resists therapy and lasts into adulthood. Based on some statistical evidence, Patients with XLT either have mild transient eczema or do not have any of these symptoms. It has been hypothesized that defects in the chemotaxis of DC and Langerhans cells, which are responsible for presenting specific (probably bacterial) antigens to T lymphocytes, cause eczema. Eczema is more complex in families with a history of atopic disease because the findings suggest that genes involved in allergic processes may have a modulatory effect [19, 20].

**185**

surveillance [26].

*Wiskott-Aldrich Syndrome*

**4.6 Malignancies**

with WAS [24].

*DOI: http://dx.doi.org/10.5772/intechopen.97220*

According to collected data, autoimmunity is a frequent occurrence in patients with WAS. Reports indicate that 40% of patients with WAS develop autoimmunity and that many patients show various forms of autoimmune disease. A study affirms that Two-thirds of WAS patients who show autoimmune manifestations develop multiple autoimmune disorders. Autoimmune hemolytic anemia (14%), vasculitis (13%), renal disease (12%), and chronic arthritis (10%) are the most common manifestations of autoimmunity in WAS [5]. Autoimmunity in WAS may be due to the formation of autoantibodies or the presence of autoreactive T cell clones. Moreover, disorders in the homeostasis of regulatory T cells and B lymphocytes can lead to autoimmune disorders in WAS patients. Generally, the incidence of autoimmune disease is lower XLT than in classic WAS. A broad spectrum of autoantibodies has been detected both in classic WAS and in XLT. For example, high serum IgM levels are a risk factor for the development of autoimmune disease and early death [21, 22].

Malignancies can occur during childhood, whereas it is most likely to appear in adolescents and young adults with the classic WAS phenotype. B cell lymphoma (often Epstein-Barr virus-positive), leukemia, myelodysplasia, and myeloproliferative disorders are among the most frequent malignancies [6, 23]. Based on a cohort study, 13% of patients with WAS developed malignancy at a mean age of 9.5 years, and only 1 of 21 patients who developed a malignancy was alive more than two years after diagnosis [5]. The incidence of malignancies in patients with XLT phenotype is ambiguous and less than in classic WAS. In WAS patients, the prevalence of non-Hodgkin lymphoma (NHL) is more common than Hodgkin lymphoma (HL) [23]. Several NHL, such as Burkitt lymphoma and lymphoblastic lymphoma, have been reported rarely among patients with WAS. The aggressive nature of malignancy in the WAS patients represents a poor prognosis, as data demonstrate 95% mortality among patients. It should be noted that genetic susceptibility due to malfunction of WASp, associated abnormalities in tumor-surveillance mechanisms (e.g., impairment in NK cell cytotoxicity), and environmental factors (e.g., Epstein–Barr virus [EBV]) are significant components that increase the risk of malignancy in patients

XLT is assumed as congenital thrombocytopenia that is sometimes intermittent (IXLT). In such cases, the eczema is usually mild. Generally, XLT patients have got a benign disease as well as excellent survival in contrast to patients with WAS. serious hemorrhage in 13.9%, life-threatening infections in 6.9%, autoimmunity in 12.1%, and malignancy in 5.2% of XLT patients at median ages of 4.9 years, 24.8 years, 12.2 years, and 34.0 years, respectively. Every male with thrombocytopenia and small platelets should be evaluated for WASp expression and WAS gene mutations [25]. XLN presents mainly as a congenital and severe form of neutropenia. Unlike

WAS, infectious complications due to T-cell immunodeficiency are absent. Impairments in immune function are similar to those explained for WAS. Nevertheless, Decreased NK cell count is a valid finding in XLN patients. Also, a slight decrease in platelet count has been reported. The potential risk of myelodysplastic syndrome and chronic myelocytic leukemia exists, which needs regular

**4.7 X-linked thrombocytopenia and X-linked neutropenia**

**4.5 Autoimmune manifestations**
