Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet counts), immune deficiency, and bloody diarrhea (due to the low platelet counts). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954.^[1]

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Signs and symptoms

WAS generally becomes symptomatic in children. Due to its mode of inheritance, the overwhelming majority are male. It is characterised by bruising caused by thrombocytopenia (low platelet counts), small platelet size on blood film, eczema, recurrent infections, and a propensity for autoimmune disorders and malignancies (mainly lymphoma and leukemia).

In Wiskott-Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts. Splenomegaly is not an uncommon finding. Also, patients develop a type of itchy rash called eczema. Autoimmune disorders are also found in patients with WAS.

Diagnosis

The diagnosis is made on the basis of clinical parameters, the blood film and low immunoglobulin levels. Typically, immunoglobulin M (IgM) levels are low and IgA and IgE levels are elevated; paraproteins are occasionally observed.^[2] Skin immunologic testing (allergy testing) may reveal hyposensitivity. It must be remembered that not all patients will have a family history, since they may be the first to harbor the gene mutation. Often, leukemia may initially be suspected on the basis of the low platelets and the infections, and bone marrow biopsy may be performed. Decreased levels of Wiskott-Aldrich syndrome protein and/or confirmation of a causative mutation provides the most definitive diagnosis.

Classification

Jin et al (2004) employ a numerical grading of severity:^[3]

• 0.5: intermittent thrombopenia
• 1.0: thrombopenia and small platelets
• 2.0: thrombopenia and normally responsive eczema or occasional upper respiratory tract infections.
• 2.5: thrombopenia and therapy-responsive but severe eczema or airway infections requiring antibiotics
• 3.0: both eczema and airway infections requiring antibiotics
• 4.0: eczema continuously requiring therapy and/or severe or life threatening infections
• 5.0: autoimmune disease or malignancy in an XLT/WAS patient.

Pathophysiology

Wiskott-Aldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASP). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASP mutations, but different ones from those that cause full-blown Wiskott-Aldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASP gene.

The WASP gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). Its exact function is being investigated, but signal transduction and cytoskeleton maintenance have been suggested.

The immune deficiency is caused by decreased antibody production, although T cells are also affected (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses.

The type of mutation to the WASP gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASP.^[3] Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASP carry a higher risk.

Epidemiology

The combined incidence of WAS and XLT is about 4-10 in 1 million live births. There is no geographical factor.

Treatment

Treatment of Wiskott-Aldrich syndrome is based on correcting symptoms. Aspirin and other non-steroidal anti-inflammatory drugs should be avoided, since these may interfere with platelet function. A protective helmet can protect children from bleeding into the brain which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or a splenectomy. For patients with frequent infections, intravenous immunoglobulins (IVIG) can be given to boost the immune system. Anemia from bleeding may require iron supplementation or blood transfusion.

As Wiskott-Aldrich syndrome is primarily a disorder of the blood-forming tissues, a hematopoietic stem cell transplant, accomplished through a cord blood or bone marrow transplant offers the only hope of cure. This may be recommended for patients with HLA-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.

History

The syndrome is named after Dr Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954,^[1] and Dr Alfred Wiskott, a German pediatrician who first noticed the syndrome in 1937.^[4] Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006 a German research group analysed family members of Wiskott's three cases, and surmised that they probably shared a novel frameshift mutation of the first exon of the WAS gene.^[5]

References