Wiskott-Aldrich Syndrome ?>

Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome


Introduction
Background

Wiskott-Aldrich syndrome (WAS) is a condition with variable expression, but commonly includes immunoglobulin M (IgM) deficiency. WAS always causes persistent thrombocytopenia and, in its complete form, also causes small platelets, atopy, cellular and humoral immunodeficiency, and an increased risk of autoimmune disease and hematologic malignancy.1 In one study of 154 patients with WAS, only 30% had a classic presentation with thrombocytopenia, small platelets, eczema, and immunodeficiency; although 84% had clinical signs and symptoms of thrombocytopenia, 20% had only hematologic abnormalities, 5% had only infectious manifestations, and none had eczema exclusively.2 WAS is an X-linked recessive genetic condition; therefore, this disorder is found almost exclusively in boys. WAS has been the focus of intense molecular biology research, which recently led to the isolation of the affected gene product.3
Pathophysiology

WAS results from an X-linked genetic defect in a protein now termed Wiskott-Aldrich syndrome protein (WASp). The gene resides on Xp11.22-23, and its expression is limited to cells of hematopoietic lineage.3 The exact function of WASp is not fully elucidated, but it seems to function as a bridge between signaling and movement of the actin filaments in the cytoskeleton. Researchers identified many different mutations4 that interfere with the protein binding to Cdc42 and Rac GTPases, among other binding partners, most of which are involved in regulation of the actin cytoskeleton of lymphocytes.3 This ultrastructural component of cellular architecture is involved fundamentally in intracellular and cell substrate interactions and signaling via its role in cell morphology and movement. The actin cytoskeleton is responsible for cellular functions such as growth, endocytosis, exocytosis, and cytokinesis.

Researchers propose several models of actin assembly; this topic is an extremely active area of cell biology research.5 Actin filament growth occurs by rapid monomer addition (polymerization) to the barbed leading end of a nucleated site. Nucleation, the rate-limiting step, is stimulated by a complex of actin-related protein Arp2/3 and WASp. Cdc42 GTPase also interacts with WASp to increase this nucleation. Next, gelsolin (activated by Ca++) severs actin filaments to create barbed ends, but then must be uncapped from the filament by phosphatidylinositol 4,5-bisphosphonate and Rac to proceed with polymerization. WASp also interacts with Rac and, thus, is involved in regulation of this process at multiple interrelated sites. WAS neutrophils have been reported to manifest abnormal NAD(P)H autofluorescence, indicating defective intracellular energy flux. Presumably, WASp mutations interfere with the proper signaling and growth of cells of the hematopoietic lineage,resultinginthe platelet and immune defects observed clinically, although the exact mechanisms and defective pathways remain largely unknown.

Recently published research demonstrates that the Cdc42-WASp interaction is necessary for certain chemoattractant-induced T-cell chemotaxis.6 Further studies have now demonstrated abnormal migration and motility in multiple key cellular components of the immune system (specifically, dendritic cells and neutrophils, as well as both B and T lymphocytes).7, 8 With regard to WASp-deficient neutrophil adhesion and migration abnormalities, this may be caused by profound defects in clustering beta-2 integrins.9 Also of note, CD43 (a major T-cell sialoglycoprotein) is located on microvilli; disruption of WASp regulation of cytoskeletal structure may be the cause of the CD43 defects often observed in patients with WAS.10 WASp may also have a role in transcriptional signaling and regulation of NK cells, independent of its functions in cytoskeletal actin polymerization.11

Studies of genotype-phenotype correlation in WAS and closely related conditions, with detailed analyses of WASp expression, have now linked absent WASp expression to classic WAS, mutant WASp expression to X-linked thrombocytopenia, and WASp with missense mutations at the Cdc42-binding site to X-linked neutropenia.12, 13, 14 Extensive study is also underway to further identify and characterize important WASp-associated proteins, such as WASp-interacting protein (WIP)15, 16, 17 and several Wiskott-Aldrich syndrome proteins verprolin homologous (WAVE).18, 19

Frequency
United States

Incidence is 4 cases per 1 million live male births, which remained relatively unchanged from 1947-1976.20
International

A study from Switzerland reported the incidence of WAS is 4.1 cases per 1 million live births. The same study also examined the prevalence of WAS in several national registries (ie, Italy, Japan, Switzerland, Sweden) and found that this condition occurred in 2-8.8% of patients with primary immunodeficiencies, although this statistic is subject to ascertainment bias.21 A similar range has been documented in a national registry in Ireland, as well.22
Mortality/Morbidity
Median survival has increased from 8 months (patients born before 1935) to longer than 6 years (patients born after 1964).20 In one recent case series, 94 surviving patients ranged in age from 1-35 years, with a median of 11 years; the average age of patients who died was 8 years.2
The cause of death is largely infections or bleeding, but, in one series, 12% of patients developed malignancies, primarily lymphoreticular tumors, and leukemia. In that series, the relative risk of malignancy was more than 100-fold that of normal and the risk increased with age.20 Another study showed similar results, with the reported cause of death among patients who did not receive bone marrow transplants being infection (44%), bleeding (23%), or malignancy (26%).2
With aggressive care (eg, splenectomy), longer survival is possible. Bone marrow transplant can be curative.23 Survival rates after stem cell transplant have continued to improve, particularly after more recent emphasis on performing these procedures as soon as possible after diagnosis.24, 25
Race
One large series of 301 confirmed and probable cases of WAS from 149 families reported that 8 families were black and 4 families were Chicano. Of the 40 families whose ancestry was traced outside North America, 38 emigrated from Europe.20
Sex
WAS is an X-linked recessive genetic disorder. The abnormal gene is relatively rare, and affected individuals often do not survive childhood.
WAS occurs almost exclusively in males, although it is also reported in females. One report of WAS in an 8-year-old girl found a WASp gene mutation on her paternal X chromosome associated with nonrandom inactivation of her maternal X chromosome.26
Age
WAS is a severe congenital immunodeficiency; therefore, it occurs primarily in children. However, 2 large case series reported patients in their fourth decade of life.20, 2
Clinical
History
Male infants with WAS usually present with bleeding, commonly bloody diarrhea, prolonged bleeding from circumcision, purpura, or unusual bruising.
One series of 154 patients found petechiae or purpura in 78%, serious gastrointestinal bleeding (hematemesis or melena) in 28%, epistaxis in 16%, and intracranial bleeding in 2% of patients.2
Serious infections also occur. Encapsulated organisms are frequent pathogens that may cause life-threatening complications, including pneumonia, meningitis, and sepsis. Pneumocystis carinii and viral infections also may become troublesome.
Atopic symptoms are frequently present, and eczema develops in 81% of these patients.2 The eczema may improve as the patient gets older, although serious complications such as secondary infection (eg, cellulitis, abscess) or erythroderma can occur.27
Physical

Watch for signs of bleeding, infection, malignancy, and atopy during the physical examination.
Patients’ general appearance and vital signs are important. Follow height and weight over time to monitor appropriate development.
Examine the skin for any evidence of eczema, purpura (eg, thrombocytopenia), or superficial or deep infections (eg, impetigo, cellulitis, furuncles, abscesses).
During head and neck examinations, note any abnormalities of the tympanic membranes (eg, otitis media) or sinuses and mucous membranes (eg, sinonasal infections, pharyngitis, thrush).
Auscultate lungs carefully to check for wheezing (eg, asthma) and rales or rhonchi (eg, pulmonary infection such as bronchitis or pneumonia).
Investigate for a possible malignancy if adenopathy or hepatosplenomegaly is present.
Neurological examination is particularly relevant if meningitis, central nervous system lymphoma, or intracranial bleeding or infection is considered.
Causes
WAS is caused by various mutations in the gene coding for the WASp. This mutation is expressed in hematopoietic cells (eg, lymphocytes) and impairs the normal function of WASp in actin polymerization.3
The WASp gene is located on the Xp11.22-23 region of the X chromosome and is inherited in a sex-linked fashion. A male child of a female carrier has a 50% chance of being affected; a female child has a 50% chance of being a carrier.28

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