Wiskott-Aldrich Syndrome: Causes, Complications and Treatment.

Definition

Wiskott-Aldrich syndrome is characterized by abnormal immune system function (immune deficiency) and a reduced ability to form blood clots. This condition primarily affects males. Individuals with Wiskott-Aldrich syndrome have micro thrombocytopenia, which is a decrease in the number and size of blood cell fragments involved in clotting (platelets). This platelet abnormality, which is typically present from birth, can lead to easy bruising or episodes of prolonged bleeding following minor trauma.

Wiskott-Aldrich syndrome causes many types of white blood cells, which are part of the immune system, to be abnormal or nonfunctional, leading to an increased risk of several immune and inflammatory disorders.

Background

Wiskott-Aldrich syndrome is named after two physicians who originally described the condition. Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by the clinical trial of micro thrombocytopenia, eczema, and recurrent infections. In 1937, Alfred Wiskott, a German pediatrician, first described three brothers who had chronic bloody diarrhea, eczema, and recurrent ear infections. All three brothers died before the age of 2 years from bleeding or infection. Later, in 1954, Robert Aldrich, an American pediatrician, reported a Dutch kindred of boys who all died of similar clinical symptoms described by Wiskott, clearly demonstrating an X-linked mode of inheritance. Forty years later, the gene responsible for WAS was identified on the short arm of the X chromosome (Xp11.22-p11.23) by linkage analysis.

 

The gene product, Wiskott – Aldrich syndrome Protein (WASp) is a 502 amino acid protein expressed within the cytoplasm of non-erythroid hematopoietic cells. More than 300 unique mutations in the WAS gene have been identified. The most common mutations are missense mutations, followed by nonsense, splice-site, and short deletion mutations. In general, WAS gene mutations that cause absent protein expression result in classic WAS. Reduced WASp protein expression results in X-linked thrombocytopenia. WASp activating gain-of-function mutations result in X-linked neutropenia.

Epidemiology

Wiskott – Aldrich syndrome occurs almost exclusively in boys with an incidence of 4 in 1 million live male births in the U.S. with a few girls being affected. There are approximately 500 WAS patients in the U.S.  The disease has a similar incidence in countries around the world.   Although the reporting data are probably incomplete, the incidence has remained stable over the last several decades.

Causes of Wiskott-Aldrich Syndrome

• When the mutation happens on the X chromosome – one of the two chromosomes, X and Y that determine a person’s gender – it can be passed on by mothers to their sons.
• WAS develops as the result of a defect in a gene located on the X chromosome. Because females have two X chromosomes, but males have only one, women who carry a defect of the WAS gene in one of their X chromosomes do not develop symptoms of the disease (because they have a “healthy” X chromosome), but can pass the defective gene on to their male children. As a result, WAS almost always affects boys only.

Symptoms of WAS

Individuals with WAS can develop different symptoms. Some people have all three classic symptoms; including: low platelets, immunodeficiency, and eczema while others experience only low platelet counts and bleeding. All are related to the mutation of the WAS gene.

• Bleeding: A reduction in the size and number of platelets is a hallmark of WAS. These small platelets are unique to WAS, and their presence is useful in making a diagnosis. Bleeding into the skin may cause bluish-red spots (called petechiae) ranging in size from small pinheads to large bruises.

 

• Infections: Ear infections, sinus infections and pneumonia are common in WAS due to the deficiency of both B and T lymphocyte function. More severe infections of the bloodstream may also occur, as well as meningitis or severe viral infections.
• Eczema: People with classic WAS frequently suffer from eczema. In infants, the eczema may resemble “cradle cap” or severe diaper rash; in older boys, it may be limited to the skin creases around the front of the elbow, around the wrist and neck, and behind the knee.
• Autoimmune manifestations: A high incidence of “autoimmune-like” (conditions that result from the unhealthy immune system attacking the patient’s own body) symptoms are common in both infants and adults with WAS. The most common of these are vasculitis, an inflammation of the blood vessels; hemolytic anemia, where the body destroys its own blood cells; and idiopathic thrombocytopenia purpura (ITP), where the immune system attacks the platelets.
• Malignancies: Cancer can occur more frequently in patients with WAS. Most of these cancers, such as lymphoma or leukemia, involve the B cells.

Complications of WAS

• Pneumonia
• Eczema (atopic dermatitis)
• Chronic, bloody diarrhea
• Ear and sinus infections
• Viral infections like herpes, cytomegalovirus (CMV) and Epstein-Barr virus (EBV)
• Many other types of infection

Diagnosis of Wiskott-Aldrich Syndrome

Examination for Wiskott-Aldrich disease includes evaluation for/of the following:

• Signs of bleeding, infection, malignancy, and atopy
• General appearance and vital signs
• Height and weight growth parameters
• Head and neck assessment
• Dermatologic assessment
• Pulmonary assessment
• Neurologic assessment

Laboratory Tests

Laboratory studies used in the evaluation of Wiskott-Aldrich syndrome include the following:

• CBC count: Often supports the diagnosis
• Quantitative serum immunoglobulin levels
• Functional testing of the humoral and cellular components of the immune system
• Delayed-type hypersensitivity skin tests
• Genetic testing
• Cultures (eg, blood) and sensitivities
• Renal function tests
• Hepatic function tests
• Major histocompatibility tests of the patient, parents, and siblings to determine feasibility for stem cell transplantation
• Screening of patient and potential donor for infectious agents (eg, HIV, CMV, hepatitis viruses)

Imaging studies

• Radiography, particularly of the chest.
• CT and MRI studies are not usually utilized for Wiskott-Aldrich syndrome unless stem cell reconstitution procedures have been performed and post transplantation complications have developed.

Treatment and management options for Wiskott-Aldrich syndrome

• Haemopoietic stem cell transplant, which is usually a bone marrow transplant, is curative for Wiskott-Aldrich syndrome patients.

Pharmacotherapy

Medications used in the treatment of Wiskott-Aldrich disease include the following:

• Antibiotics (eg, amoxicillin, amoxicillin/clavulanate, cefuroxime, ceftriaxone, vancomycin, nafcillin)
• Inhaled bronchodilators (eg, albuterol, salmeterol, beclomethasone, fluticasone)
• Hyperimmune globulins (eg, varicella-zoster immune globulin)
• Immunizations (eg, vaccines, including diphtheria and tetanus toxoids [DT or Td], acellular pertussis, conjugated HIB, conjugated pneumococcal vaccine, unconjugated meningococcal A and C, hepatitis B [HBV], influenza)
• Corticosteroids (eg, prednisone, methylprednisolone, fluocinolone)
• Immunoglobulins (eg, immune globulin)

Surgery

Surgical intervention may be necessary for complications of bleeding, such as the following:

• Neurosurgery if subdural hematoma forms
• Surgical evacuation of hematomas
• Surgical intervention to halt blood loss after any minor trauma
• Splenectomy as an option in cases of coexisting severe thrombocytopenia and frequent bleeding when stem cell reconstitution is not considered

Additional treatments

Supportive care in patients with Wiskott-Aldrich syndrome includes the following:

• Transfusions of platelets and/or red blood cells
• Bone marrow transplantation
• Infusions of intravenous immunoglobulin G

Prevention of Wiskott-Aldrich Syndrome

• Primary Prevention: Pneumococcal vaccine is recommended presplenectomy for all children <2 years, and for unvaccinated children between 24 and 59 months old who are at high risk for pneumococcal infections, if they are not on immunoglobulin therapy. Splenectomy necessitates penicillin prophylaxis for life.
• Secondary Prevention: Mutation analysis for other family members, either if history suggestive of WAS or to detect carrier status.