Pediatric Wiskott-Aldrich Syndrome Clinical Presentation

Updated: Apr 03, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
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Presentation

History

The characteristic triad of bleeding, eczema, and recurrent infections generally become evident during the first year of life. However, only one third of patients with WASP mutations express the classic triad of Wiskott-Aldrich syndrome (WAS).

The first clinical signs are petechiae (see the image below) and ecchymoses of the skin and oral mucosa and bloody diarrhea. Patients may have prolonged bleeding after circumcision or from the umbilical stump. CNS bleeding occurs in fewer than 2% of patients but may occur at birth or later due to minor trauma. One series of 154 patients found petechiae or purpura in 78%, serious GI bleeding (hematemesis or melena) in 28%, epistaxis in 16%, and intracranial bleeding in 2% of patients. [2]

This 1-year-old boy was hospitalized because of re This 1-year-old boy was hospitalized because of respiratory syncytial virus bronchiolitis but was noted to have eczema and petechiae (note arrow). His history was significant for a subdural hematoma for which trauma was denied; at that time the platelet count was 212,000. His diagnosis of Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a missense mutation (Phe 128 Ser).

With the loss of maternally transported immunoglobulin G (IgG), infants begin to have infections, most commonly otitis media, at 4-8 months. Pneumonia, sepsis, and meningitis are caused by polysaccharide-coated bacteria, predominantly Streptococcus pneumoniae,Haemophilus influenzae type b (Hib), and Staphylococcus aureus.

Less commonly, gram-negative bacteria such as Klebsiella pneumoniae and Escherichia coli are etiologic agents for sepsis or meningitis. Viral infections may be unusually severe. Herpes simplex often causes mucocutaneous infections, and varicella-zoster virus may be life-threatening. Opportunistic infections such as Pneumocystis carinii have been reported but are rare. Fungal infections are usually restricted to mucocutaneous candidiasis.

Atopic symptoms are frequently present, and eczema develops in 81% of these patients. [2] Eczema ranges from mild to severe, and patients usually present earlier than immunocompetent infants. The eczema may improve as the patient gets older, although serious complications such as secondary infection (eg, cellulitis, abscess) or erythroderma can occur. [28] Milk and other food allergies have been associated with eczema in Wiskott-Aldrich syndrome. Eczema may worsen in the presence of infection; it also follows the typical pattern of worsening in the winter. Although the dermatitis often clinically mimics atopic dermatitis, it is generally more exfoliative. Conventional topical care with moisturizing creams and steroids have moderate benefit. Other atopic disorders, reactive airway disease (typically in toddlers), and allergic rhinitis (typically in school-aged children) are also common.

Autoimmune disorders, particularly autoimmune hemolytic anemia (AIHA), can be observed in patients of any age. In some cases, infections seem to aggravate AIHA. Arthritis, nephritis, and immune thrombocytopenia and neutropenia are also increased in incidence.

Lymphomas and leukemias constitute most malignancies, although various other malignancies are reported. Patients can present in mid childhood. The risk of malignancy seems to increase with age. The most common malignancy is non-Hodgkin lymphoma. Aggressive mature B-cell lymphoproliferative disease may be evident in children and adults with WAS. [29]

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Physical

Watch for signs of bleeding, infection, malignancy, and atopy during the physical examination. The patients' general appearance and vital signs are important. Follow height and weight over time to monitor appropriate development. Patients usually experience normal growth for the first several years of life, even with episodes of severe acute infections

Examine the skin for any evidence of eczema. The face, scalp, and flexural areas are most commonly involved. Superficial or deep infections such as secondary bacterial infections (eg, impetigo, cellulitis, furuncles, abscesses), eczema herpeticum, and molluscum contagiosum are common. Also check the skin for purpura (thrombocytopenia). The presence of lower extremity ecchymoses in infants (see the image below) who are not yet walking indicates a platelet abnormality. Examine for bloody diarrhea in the absence of an infectious etiology. Other manifestations may include hematemesis, melena, epistaxis, and hematuria.

This 10-month-old infant presented with bloody dia This 10-month-old infant presented with bloody diarrhea at age 4 months followed by recurrent otitis media infections. A maternal uncle had Wiskott-Aldrich Syndrome (WAS). Note the mild malar eczema and pretibial ecchymoses in this nonambulatory child. His diagnosis was confirmed by immunologic parameters, thrombocytopenia, and low platelet volume.

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). The older infant often has a dramatically increased incidence of otitis media, although it responds appropriately to oral antibiotics.

Carefully auscultate the lungs to check for wheezing (eg, asthma) and rales or rhonchi (eg, pulmonary infection such as bronchitis or pneumonia).

Clinical signs of anemia, paleness, tachycardia, and even jaundice can be caused by blood loss or AIHA. Renal failure, presumably secondary to glomerulonephritis, should also be considered as a potential cause for anemia.

Investigate for a possible malignancy if adenopathy or hepatosplenomegaly is present.

Neurological examination is particularly relevant if meningitis, CNS lymphoma, or intracranial bleeding or infection is considered.

Cutaneous vasculitis may be rarely seen as recurrent acute hemorrhagic edema of infancy. [30]

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Causes

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. Theoretically, female carriers of WASP mutations could have clinical illness if extreme lyonization occurs, [31] but nonrandom X inactivation is characteristic for carriers. Wiskott-Aldrich syndrome is caused by various mutations in the gene that code for the WASp. This mutation is expressed in hematopoietic cells (eg, lymphocytes) and impairs the normal function of WASp in actin polymerization. [15] Eczema appears to be related to the abnormal function of the T cells.

Mutations can occur in any of the 12 exons of the WASP gene. Approximately one half of the reported mutations are single-base pair substitutions, often within CpG dinucleotide hot spots. Half of the mutations have been identified within the first 3 exons. Milder disease has been reported for mutations in exons 1 and 2.

A strong phenotype-genotype correlation was discovered, with classic Wiskott-Aldrich syndrome occurring when WASp is absent, X-linked thrombocytopenia occurring when mutated WASp is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site; however, exceptions are noted. [2, 32]

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