**4.2 Thrombocytopenia**

It is the foremost common finding present at the time of diagnosis and appears at birth. However, the severity is variable. Approximately 50% of patients with WAS will have severe Thrombocytopenia with a platelet count<20,000/μL. Furthermore, the severity of Thrombocytopenia has a close relationship with bleeding. Bleeding events occur in >80% of WAS patients. These bleeding complications consist of non-life-threatening (e.g, ecchymosis, hematemesis, epistaxis, petechiae, etc.) and or life-threatening (eg, gastrointestinal and intracranial hemorrhage). life-threatening bleeding happens in 30% of patients. However, intracranial hemorrhage occurs in exactly 2% of cases. Although Megakaryocyte numbers are typically

**183**

**4.3 Immunodeficiency**

*Wiskott-Aldrich Syndrome*

Autoimmunity and/or malignancies

*severe, life-threatening infections.*

*are less in XLT than in WAS.*

*Infections typical for neutropenia.*

*requiring continuous antibiotic prophylaxis.*

WASP expression Absent or

HSCT Yes at an

truncated

early age

*Clinical phenotype associated with mutations of the WASP gene [acc.19].*

Phenotype

Treatment

*\**

*†*

*‡*

**Table 1.**

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

normal in patients with WAS, platelet formation changes into abnormal. It should be noted that the role of anti-platelet antibodies in platelet destruction and maintaining thrombocytopenia isn't negligible. As an example, a group of infants less than or equal to 2 years of age may present with "severe refractory thrombocytopenia," probably due to antiplatelet autoantibody. Moreover, disruptions in platelet function as well as remarkable and may give rise to bleeding and diminished platelet survival. WASp plays a key role in the process of platelet formation, activation, and associated cytoskeletal remodeling so that failure in platelet production and function is attributed to it. Increased expression of phosphatidylserine on the surface of circulating platelets has been interpreted as a sign of increased phagocytosis and destruction of platelets within the spleen in WAS/XLT. Whereas, decreased platelet

**WAS XLT IXLT XLN**

Frequent Possible - -

Present, normal quantity

No ?

Present

Thrombocytopenia + + (+) - Small platelets + + + - Eczema +/++/+++ -/+ - - Immune deficiency +/++ -/(+) - - Infections - +\*

Congenital neutropenia - - - + Disease scores 3,4, or 5 1,2, or (5)† <1 0

IVIG Yes No (with exceptions) No No

Splenectomy No Might be considered‡ No No

*Patients with XLT with a score of 1 or 2 might progress to a score of 5. Incidence of autoimmunity and malignancies* 

*Splenectomy results in increased platelet numbers and reduced bleeding but causes a marked increase in sepsis,* 

*IXLT, Intermittent XLT; HSCT, hematopoietic stem cell transplantation; XLN, X-linked neutropenia. Scoring system: -/ (+), absent or mild; -/+, intermittent thrombocytopenia; (+), mild, transient eczema or mild, infrequent infections not resulting in sequelae; +, thrombocytopenia, persistent but therapy-responsive eczema, and recurrent infections requiring antibiotics and often IVIG prophylaxis; ++, eczema that is difficult to control and* 

Present, reduced quantity

Might be considered if there is a sibling donor

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

production resulting from ineffective thrombocytopoiesis [6–8].

#### *Wiskott-Aldrich Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97220*

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

Wiskott-Aldrich syndrome is caused by mutations of the gene WASP (WAS protein) involved in actin polymerization, cellular signaling, cytoskeletal rearrangement, and immunological synapse formation. These mutations cause changes in protein structure by different mechanisms and lead to different phenotypes of

It has been estimated that one in every 100,000 male births leads to Wiskott-Aldrich Syndrome, and in families without a history of the disease, the average age of diagnosis is 24 months [4, 5]. In the United States, the estimated incidence of WAS is one in 250,000 male births. Whereas WAS still is a rare disease, it is more common than other immunodeficiency syndromes such as hyper-IgM syndrome or SCID which have an estimated incidence of about one in 1,000,000 live births. It is thought WAS accounts for 1.2% of all inherited immunodeficiencies in the United States [6]. Up to now, the impact of any ethnic or geographical factor on its incidence has not been reported. Because of misdiagnosing of mild cases, these

conditions may be presumed as idiopathic thrombocytopenia purpura [4].

system, we have delineated different clinical phenotypes (**Table 1**).

The incidence of the classic WAS phenotype has been estimated at 1 in 100,000 individuals. Based on clinical manifestations, WAS-XLT commonly is presented at birth and consists of bruising, bloody diarrhea as well as petechiae. Excessive bleeding consequent circumcision can be considered as an early diagnostic sign. Furthermore, during infancy and childhood, eczema is a frequent manifestation of patients with classic WAS. Small platelet and thrombocytopenia are the most reliable finding in WAS and XLT phenotype. A variety of infections such as bacterial pneumonia, skin infections as well as otitis media with drainage of mucoid material are common complaints. XLT patients are less likely to have problems such as eczema and infection and oftentimes are misdiagnosed with Idiopathic thrombocytopenic purpura (ITP). Patients with X-linked neutropenia caused by missense mutations in the Cdc42-binding domain are affected at birth. However, their symptoms do not resemble those of classic WAS or XLT. Through a simple scoring

It is the foremost common finding present at the time of diagnosis and appears at birth. However, the severity is variable. Approximately 50% of patients with WAS will have severe Thrombocytopenia with a platelet count<20,000/μL.

Furthermore, the severity of Thrombocytopenia has a close relationship with bleeding. Bleeding events occur in >80% of WAS patients. These bleeding complications consist of non-life-threatening (e.g, ecchymosis, hematemesis, epistaxis, petechiae, etc.) and or life-threatening (eg, gastrointestinal and intracranial hemorrhage). life-threatening bleeding happens in 30% of patients. However, intracranial hemorrhage occurs in exactly 2% of cases. Although Megakaryocyte numbers are typically

**4. Clinical and pathological manifestations**

**4.1 Incidence and clinical phenotypes**

**4.2 Thrombocytopenia**

**2. Etiology**

this disease [1, 2].

**3. Epidemiology**

**182**


*IXLT, Intermittent XLT; HSCT, hematopoietic stem cell transplantation; XLN, X-linked neutropenia.*

*Scoring system: -/ (+), absent or mild; -/+, intermittent thrombocytopenia; (+), mild, transient eczema or mild, infrequent infections not resulting in sequelae; +, thrombocytopenia, persistent but therapy-responsive eczema, and recurrent infections requiring antibiotics and often IVIG prophylaxis; ++, eczema that is difficult to control and severe, life-threatening infections.*

*\* Infections typical for neutropenia.*

*† Patients with XLT with a score of 1 or 2 might progress to a score of 5. Incidence of autoimmunity and malignancies are less in XLT than in WAS.*

*‡ Splenectomy results in increased platelet numbers and reduced bleeding but causes a marked increase in sepsis, requiring continuous antibiotic prophylaxis.*

#### **Table 1.**

*Clinical phenotype associated with mutations of the WASP gene [acc.19].*

normal in patients with WAS, platelet formation changes into abnormal. It should be noted that the role of anti-platelet antibodies in platelet destruction and maintaining thrombocytopenia isn't negligible. As an example, a group of infants less than or equal to 2 years of age may present with "severe refractory thrombocytopenia," probably due to antiplatelet autoantibody. Moreover, disruptions in platelet function as well as remarkable and may give rise to bleeding and diminished platelet survival. WASp plays a key role in the process of platelet formation, activation, and associated cytoskeletal remodeling so that failure in platelet production and function is attributed to it. Increased expression of phosphatidylserine on the surface of circulating platelets has been interpreted as a sign of increased phagocytosis and destruction of platelets within the spleen in WAS/XLT. Whereas, decreased platelet production resulting from ineffective thrombocytopoiesis [6–8].
