Wiskott-Aldrich Syndrome

What is Wiskott-Aldrich Syndrome (WAS)?

Wiskott-Aldrich Syndrome is a rare syndrome defined by an immune deficiency, reduced blood clot formation, eczema, low platelet count, bloody diarrhea and recurrent infections.

WAS is known as an X linked disorder. This syndrome is also known as eczema-thrombocytopenia-immunodeficiency syndrome. ^{[1, 3, 4]}

Background

It is named Wiskott-Aldrich syndrome after its founders, Alfred Wiskott and Robert Aldrich. Alfred Wiskott was a German pediatrician. Robert Aldrich was an American pediatrician. Both described early cases of the syndrome.

Forty years after their first discoveries of the syndrome, the responsible gene was found to be on the X chromosome. This gene is a five hundred two amino acid protein on the cytoplasm of non-erythroid hematopoietic cells. There are more than three hundred different mutations found on the WAS gene. These mutations include missense, nonsense, splice site and short deletion mutations.

Depending on the specific mutations across the gene, there is a wide variety of disease that can result. ^[1]

People affected with WAS have micro-thrombocytopenia (decreased size and number of platelets). This platelet abnormality that occurs since birth causes easy bruising and prolonged bleeding from minor trauma. WAS causes white blood cell abnormalities and malfunctioning which leads to increased risk of immune and inflammatory disorders.

Many people with Wiskott-Aldrich Syndrome have eczema (inflammatory skin condition). People with WAS are at a higher risk of developing an auto immune disorder and at developing some cancers such as lymphoma. Ear and sinus infections commonly affect people with WAS. WAS mostly occurs in males. ^{[1, 3, 4]}

Signs and Symptoms 

Wiskott Aldrich syndrome symptoms:

• Petechiae and purpura
• Bruising
• Random nose bleeds
• Bloody diarrhea
• Eczema
  • Eighty percent of people with WAS develop this eczema
  • Severity varies and is worse in people with family history of allergies and asthma
• Recurrent bacterial and viral infections
  • Most commonly recurrent ear infections
  • Increased risk of death from bacterial sepsis
  • Infections from opportunistic viruses/bacteria are common like herpes simplex virus, Epstein Barr virus, adenovirus and cytomegalovirus
  • Removal of the spleen increases the risk of bacterial infection
• Spleen enlargement
• Autoimmune disorders (hemolytic anemia, immune thrombocytopenic purpura, immune mediated neutropenia, rheumatoid arthritis, vasculitis and immune mediated kidney/liver damage)
  • Risk increases with age
  • Men who survive early complications of WAS develop one+ autoimmune conditions in twenty five to forty percent of the time
  • The risk for developing lymphoma increases with the presence of an autoimmune disorder
• Can develop cancer (like lymphoma)
  • Extremely increased risk of lymphoma with exposure to Epstein Barr virus
  • Usually occurs in areas like the brain, lungs or GI system
  • WAS affected individuals have about a thirteen percent chance of developing lymphoma, usually at about nine and a half years old
• Reduced IgM (Immunoglobulin M) levels
• Reduced blood clotting
• Mucosal bleeding
• Thrombocytopenia with small platelets
  • Usually present at birth
  • Intracranial bleeding is a potential risk
  • Thirty percent of males have life threatening bleeding before diagnosis
  • Thrombocytopenia can be reversed with removal of spleen
• Absent or decreased WAS protein detection
• Abnormal lymphocytes

Pictures

^{[5] [1]}

Diagnosis

A male with the following symptomology should be suspected to have WAS:

• Serious thrombocytopenia (less than 70,000 platelets/mm³)
• Small platelets (more than 2 SD below laboratory mean platelet volume)
• Recurrent bacterial, viral or opportunistic infections in infancy/childhood
• Eczema
• Autoimmune disorder
• Lymphoma
• WAS related disorder family history in one+ male family members on maternal side
• Absent or decreased Wiskott Aldrich syndrome protein detection
• Abnormal lymphocytes

An individual with the following symptomology should be suspected for X linked thrombocytopenia:

• Thrombocytopenia from birth
• Small platelet size
• No other clinical findings of WAS
• WAS related disorder family history in one+ male family members on maternal side
• Absent or decreased WAS protein detection

An individual with the following symptomology should be suspected for X linked congenital neutropenia:

• Bacterial infections, recurrent
• Neutropenia, persistent
• Bone marrow lack of development without other clinical findings of WAS
• Normal WAS protein detection

An established WAS diagnosis in a male proband has:

• Thrombocytopenia (less than 100,000 platelets/mm³)
• Small platelets

AND one or more of these:

• Eczema
• Bacterial or viral infections, recurrent
• One or more autoimmune disorders
• Malignancy
• Decreased WAS protein expression in fresh blood
• Abnormal antibody response with polysaccharide antigens/low isohemagglutinins
• Maternal family history of Wiskott-Aldrich Syndrome

AND

• Hemizygous WAS variant on molecular genetic testing

An established WAS diagnosis in a FEMALE proband has:

(Wiskott Aldrich syndrome in females)

• Hemizygous WAS variant on molecular genetic testing
• Clinical features of WAS ^[5]

Treatment

Treatment for Wiskott-Aldrich syndrome:

• Immunologist referral
• Clinical geneticist consult
• Treatment varies per person based on their clinical WAS manifestations
  • Hematopoietic cell transplantation
    • Only curative treatment for WAS with ninety percent probability cure rate
    • Candidates for this treatment have decreased WAS protein expression and a suitable donor
    • Some symptoms take months to resolve after treatment
    • Younger age at transplantation, better long term outcomes
  • Topical steroids for eczema, antibiotics may help
  • Prompt evaluation and treatment for infections
    • Empiric parenteral antibiotic treatment
    • IV immune globulin
    • Routine childhood immunizations, live vaccines avoided
    • Exhaustive investigations until source of infection is determined
  • Immunosuppressant therapy for autoimmune disorders
  • Removal of spleen
    • Palliative
    • Must take antibiotics indefinitely
  • Platelet transfusion
  • Regular blood work to watch blood count
  • New born circumcision avoidance if baby has thrombocytopenia
  • Over the counter medications must be discussed with physician
  • Gene therapy
  • Prenatal testing ^[2]

Prognosis

• Poor in the past prior to stem cell transplant
• Prognosis has improved with aggressive care
• Wiskott Aldrich syndrome life expectancy is twenty five years median with spleen removal
• Longer survival rate with successful bone marrow transplant

Reference List:

1. Medscape by E Medicine, Available from: http://emedicine.medscape.com/article/137015-overview?pa=nq%2FhR%2BhhqCnAk5hR35wt974BrVb6agUzzi8pBXOg5qMSKepTRXEW3xNZYaxsOZfvDVm2U4IehjxORyox%2BOYAPvFDqoONiUtlOtdX6maZcRI%3D
2. National Center for Biotechnology Information, US Library of Medicine, Available from: https://www.ncbi.nlm.nih.gov/books/NBK1178/
3. US National Library of Medicine, Available from: https://ghr.nlm.nih.gov/condition/wiskott-aldrich-syndrome
4. Wikipedia, Available from: https://en.wikipedia.org/wiki/Wiskott%E2%80%93Aldrich_syndrome
5. Medicalrealm, Available from: http://www.medicalrealm.net/what-is-genetic-disorder—wiskott-aldrich-syndrome.html