Wiskott-Aldrich Syndrome Clinical Presentation

Updated: Aug 24, 2017
  • Author: Peter N Huynh, MD; Chief Editor: Michael A Kaliner, MD  more...
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Presentation

History

Male infants typically present in the first year of life with severe persistent thrombocytopenia, eczema, recurrent sinopulmonary infections, and opportunistic infections. Pronounced bleeding after circumcision is an early diagnostic sign to watch out for. The most consistent laboratory finding at the time of diagnosis is thrombocytopenia and small platelets. Therefore, any male with microthrombocytopenia should be evaluated for WASp expression and WAS gene mutation. Depending on the mutations within the WASp gene product, there is wide variability of clinical disease at presentation. In one study of 154 patients with WAS, only 30% had the classic presentation with thrombocytopenia, small platelets, eczema, and immunodeficiency; 84% had clinical signs and symptoms of thrombocytopenia, 80% had eczema, 20% had only hematologic abnormalities, and 5% had only infectious manifestations. [1] Autoimmune disease is common and occurs in up to 40–70% of patients. One review of 55 patients with WAS from a single hospital in France, over a course of 20 years, found autoimmune or inflammatory conditions in 70% of patients, most commonly autoimmune hemolytic anemia (see Donath-Landsteiner Hemolytic Anemia and Cold Agglutinin Disease). [34] There is also a significantly increased risk of malignancy in WAS (10–20%), especially with B-cell lymphoma. Patients with autoimmune disease were significantly more likely to develop malignancy. [1]

Male infants with WAS usually present with bleeding, commonly bloody diarrhea, excessive bleeding after 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. [1]

Recurrent sinopulmonary infection with encapsulated organisms occur frequently and include otitis media (64%), pneumonia (25%0, sepsis (7%), and meningitis (4%).

Opportunistic infections with Pneumocystis jirovecii can occur.

Patients with WAS can also develop severe and disseminated viral infections, including herpes simplex (6%) and varicella (3%).

Atopic symptoms are frequently present, and eczema develops in 80% of these patients. [1] Severe eczema requires aggressive therapy. The eczema may improve as the patient gets older, although serious complications such as secondary infection (eg, cellulitis, abscess) or erythroderma can occur. [35]

Cutaneou infections are common and may require systemic antibiotics.

Autoimmune disease is common and occurs in up to 40–70% of patients.

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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, [36] or intracranial bleeding or infection is considered.
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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. [2] A strong phenotype-genotype correlation has been described. [37] Absent WASp protein expression results in classic WAS. Mutated WASp protein expression causes X-linked thrombocytopenia. Missense mutations at the Cdc42-binding site results in X-linked neutropenia. [11, 12, 13]

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. [38]

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Complications

Complications from infection, bleeding, autoimmune disease, and malignancy characterize WAS.

Autoimmune and rheumatologic conditions may also occur. [39] One study found these conditions in 40% of patients, and often multiple conditions coexisted in the same patient. Patients with autoimmune disease were significantly more likely to develop malignancy. [1] Another review of 55 patients with WAS from a single hospital in France, over 20 years, found autoimmune or inflammatory conditions in 72%, most commonly autoimmune hemolytic anemia (see Donath-Landsteiner Hemolytic Anemia and Cold Agglutinin Disease), among multiple other conditions. [34]

Malignancy, especially lymphoreticular, occur in 10–20% of WAS patients

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