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At a glance

This is a congenital and life-threatening medical immunodeficiency condition affecting mostly males due to its X-linked inheritance. It is characterized by severe eczema, profound thrombocytopenia, immune deficiency causing frequent infections as a result of a defect in both T- and B-cell function. Clinically, affected individuals present for bloody diarrhea and a high incidence of autoimmunity and malignancy. Death frequently occurs during childhood as a result of severe thrombocytopenia and bleeding. The Wiskott-Aldrich Syndrome (WAS)-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) are often clinical similar although the XLN is rarer. They are both caused by mutations of the same gene.

Synonyms

Aldrich Syndrome; Eczema-Thrombocytopenia-Immunodeficiency Syndrome; Aldrich-Huntley Syndrome; Aldrich-Dees Syndrome; Aldrich-Wiskott Syndrome; Wiskott Syndrome; Wiskott-Aldrich-Huntley Syndrome; Wiskott-Aldrich-Dees Syndrome.

History

Inherited immune deficiency that was first described by Alfred Wiskott (1898-1978), a German pediatrician, who first noticed this syndrome in 1937. Wiskott described three brothers with a similar disease, whose sisters were unaffected. It was subsequently characterized by Robert Anderson Aldrich (1917-1998), an American pediatrician, who described this medical condition in a family of Dutch-Americans in 1954. In 2006, a German research group analyzed family members of the Wiskott’s three cases, and surmised they probably shared a novel frameshift mutation of the first exon of the WASp gene.

Incidence

It is a rare disorder with an estimated incidence of approximately 1 to 4:100,000 live births in the general population. The incidence varies depending on the phenotype, ie, thrombocytopenic (XLT) or neutropenic (XLN), the latter one being the less frequent. The estimated incidence in the United States is one in 250,000 live male births. There is no geographical factor believed to be present. The estimated prevalence in the United States is 1.2% of patients with identified primary immune defects.

Genetic inheritance

Transmitted as an X-linked recessive trait. The gene responsible is located on the short arm of the X chromosome at Xp11.22–p11.23. The WAS gene encodes the WAS protein (WASp), which is a 501-amino acid protein expressed within the cytoplasm of nonerythroid hematopoietic cells. The phenotype is variable due to its X-linked inheritance. Males present the full clinical condition whereas females have limited symptoms or are carriers without clinical manifestations. Approximately 50% of affected individuals present mutations on the WAS gene. The other half has an X-linked thrombocytopenia (XLT) phenotype. The WAS gene mutations cause X-linked neutropenia (XLN) and are considered very rare, with less than 12 patients in four families reported to date.

Pathophysiology

Caused by mutation in the WAS gene located at Xp11.23–p11.22.

Diagnosis

Onset generally occurs before 2 years of age in a boy with hemorrhagic signs, thrombocytopenia with small-size platelets, recurrent infections, and eczema. Early prenatal diagnosis can be made by trophoblast biopsies. The ...

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