 is an X-linked disorder characterised by a triad of eczema, immune deficiency, and...){kind=link}
Wiskott Aldrich Syndrome Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterised by a triad of eczema, immune deficiency, and thrombocytopenia with small platelets (microthrombocytopenia). This syndrome occurs due to a pathogenic mutation in the WAS gene located on the short arm of the X chromosome, encoding the Wiskott-Aldrich Syndrome protein (WASp). This disorder of the immune system has a very low incidence and global prevalence. The estimated incidence of WAS is about 1 in 100,000 live births, and the disease primarily affects males without ethnic or geographical predominance. The disease usually affects males, but there is no ethnic or geographical predominance.
It has a variable presentation that ranges from the milder phenotype, such as X-linked thrombocytopenia (XLT), to classic severe WAS. Expert clinical skills are essential for accurate diagnosis. The treatment of WAS focuses on symptom control, prevention of complications, and, where possible, curative therapy with hematopoietic cell transplantation (HCT).
Etiology : Wiskott Aldrich Syndrome
A mutation in the WAS gene, which is responsible for producing the WAS protein, causes the disease. The WAS gene is present on the short arm of your X chromosome. WASp is involved in immunological synapse formation and cellular signalling. This protein exists in all the blood cells. Mutations alter the configuration of the protein, causing phenotypic variability in syndrome manifestations. WASp sends messages to your cells to attach to other cells or tissues. This attachment or adhesion helps your immune system to defeat invaders like viruses or bacteria. In case of a genetic mutation, your blood cells are not able to attach to other cells or tissues, affecting your immune system’s ability to defend itself. Phenotypic variability depends on the type of mutation, which explains the spectrum from XLT to severe WAS.
Pathophysiology
This gene produces a protein called WASp. It is important for controlling the structure and movement of immune cells by regulating the actin cytoskeleton (a framework inside cells that helps them change shape, move, and communicate). When WASp is faulty or missing due to the mutation, immune cells like T cells cannot move properly or form effective connections with other immune cells, which leads to T cell dysfunction.
This dysfunction in turn disrupts the balance and survival of other immune cells, such as B cells and natural killer (NK) cells (the B cells become depleted, and NK cells lose their ability to kill infected or abnormal cells effectively). This makes patients more prone to infections, autoimmunity, and hematologic malignancies such as lymphomaand leukemia.
Autoimmune problems in WAS happen because regulatory T cells fail to control the immune response properly, which allows harmful immune cells and autoantibodies to attack the body’s own tissues. Additionally, the body has trouble clearing dead cells, which causes ongoing inflammation. WAS also causes low platelet counts with small-sized platelets called microthrombocytes due to problems in platelet production, increased destruction of platelets (sometimes by autoantibodies), and abnormal development of bone marrow cells that produce platelets.
Clinical Phenotypic Manifestation of WAS
The main clinical phenotypic expressions of WAS include:
Classic (Severe) WAS:
It is the severe phenotype of WAS that affects males in early childhood. It presents in early childhood with bleeding (probably due to thrombocytopenia), fungal or viral infections, and extensive eczema. Hepatosplenomegaly and lymphadenopathy are common. People with classic WAS are more likely to develop autoimmune disorders, lymphoma, and other malignancies that often lead to early death.
X-linked Thrombocytopenia (XLT):
XLT presents as congenital thrombocytopenia. Eczema is usually mild, and these patients have a benign syndrome that develops with good long-term survival. Patients still carry an increased risk for severe events like life-threatening autoimmune complications, serious hemorrhage, and cancer.
X-Linked Neutropenia (XLN):
XLN presents as congenital neutropenia. Individuals with XLN present infections characteristic of neutropenia. It may also develop as an infection associated with lymphocyte dysfunction. Such patients also have a high risk of myelodysplasia.
Symptoms of Wiskott-Aldrich Syndrome
The disease manifests as:
Eczema:
Eczema (a non-contagious, inflammatory skin condition) of varying severity develops in roughly one-half of the WAS patients. It usually occurs in the first year of life. It resembles atopic dermatitis.
Ecchymosis and eczematoid lesions with bleeding in some lesions. Image Courtesy: Wiskott–Aldrich syndrome with normal platelet volume in a low-income setting: a case report by Mawalls et al, 2021, doi.org/10.1177/26330040211009905, available via https://journals.sagepub.com/doi/10.1177/26330040211009905, CC BY.
Immunodeficiency:
Its severity depends on the type of mutations and the resulting expression of proteins. Individuals present with numerous recurrent infections and failure to thrive. Infectious manifestations include:
- Colitis
- Sepsis
- Meningitis
- Pneumonia
- Sinusitis
- Otitis media
Autoimmune manifestations include:
- Anemia
- Vasculitis
- Neutropenia
- Rheumatoid arthritis
- Inflammatory bowel diseases
- Renal diseases
Malignancies can include:
- Leukemia
- Lymphoma
Thrombocytopenia:
Thrombocytopenia is the most common finding at the time of diagnosis. It can be present at the time of birth. Patients affected with this disease may present prolonged bleeding and petechiae from the umbilical stump or after circumcision. Infants below the age of 2 years can present severe refractory thrombocytopenia mainly due to antiplatelet autoantibody.
The other manifestations can include:
- Life-threatening symptoms such as intracranial, gastrointestinal, and oral bleeding.
- Hematuria
- Epistaxis
- Melena
- Hematemesis
- Purpura
Diagnosis of Wiskott-Aldrich Syndrome
A healthcare provider diagnoses WAS during infancy or childhood during a physical exam and then offers some tests for confirmation.
Physical Examination:
- Doctors look for the signs of infection, bleeding, malignancy, and atopy during physical examination. They examine the skin for evidence of eczema, superficial or deep infections, or purpura.
- They will look for the abnormalities of the tympanic membranes or sinuses and mucous membranes during neck and head examination.
- If adenopathy or hepatosplenomegaly is present, doctors investigate for a possible malignancy.
- Doctors consider a neurological examination relevant in cases of infection, intracranial bleeding, central nervous system lymphoma, or meningitis.
- They can follow the height and weight of the child over time to monitor appropriate development.
Laboratory Findings:
Laboratory assessment tests can include complete blood count, peripheral smear, and genetic blood. The abnormal laboratory findings include:
- Low platelet count accompanied by abnormally small platelet size. Generally, the platelet counts are 20,000 to 50,000 per mm³, but they can drop below 10,000 per mm³ in the case of thrombocytopenia.
- There can be a decreased number and function of regulatory T cells.
- There can be decreased natural killer cell cytotoxicity.
- Impaired neutrophil polysaccharide antigens.
- An immunoglobulin profile can show decreased Immunoglobulin (Ig) M, elevated IgE and IgA, and low or normal IgG.
- Genetic confirmation by WAS gene sequencing or deletion/duplication analysis.
- Abnormal lymph node and spleen histopathology includes T cell zone depletion and abnormal follicular architecture.
Carrier testing and genetic counseling are essential, as female carriers are usually asymptomatic but may rarely show features due to skewed X-inactivation. Prenatal and preimplantation genetic testing are available.
Management & Treatment of Wiskott-Aldrich Syndrome
The management and treatment of WAS depend on conventional and supportive care. Supportive care includes aggressive treatment of infections, eczema management, and avoidance of live vaccines due to immunodeficiency. Prophylactic antibiotics and IVIG replacement therapy are recommended for antibody deficiency.
Immune Globulin Therapy:
Doctors recommend intravenous immunoglobulin therapy for XLT and classic WAS patients with significant antibody deficiency. Doctors can also consider Subcutaneous immunoglobulin, but this route of administration requires caution because of the bleeding tendency.
Eltrombopag:
Eltrombopag is an oral thrombopoietin receptor agonist approved for treating immune thrombocytopenia. It prevents bleeding in patients with WAS waiting for hematopoietic cell transplantation (HCT) but requires caution, as data remain limited.
Hematopoietic Cell Transplantation:
HCT is the only curable treatment. The transplantation procedure involves harvesting stem cells from the bone marrow, umbilical cord, or peripheral blood following treatment with medications (medications that cause stem cells to leave the bone marrow and circulate systemically). The outcomes of HCT are better if performed before the development of malignancy or autoimmune disease. Excellent results occur in patients with partially matched cord blood donors, unrelated donors, or human leukocyte antigen (HLA) matches.
Other Treatment Options:
Some other treatment options include:
Immunosuppressive Treatment
It is necessary for autoimmune manifestations. The autoimmune cytopenias react to the monoclonal antibody rituximab. It is relatively safe for patients who are already receiving intravenous immune globulin therapy.
Splenectomy
Doctors recommend elective splenectomy in carefully chosen patients to reverse the thrombocytopenia. It aids in arresting the bleeding tendency by increasing the number of circulating platelets. However, patients who undergo splenectomy necessitate lifelong antibiotic prophylaxis. Also, they can be at a high risk of septicemia.
Gene Therapy
Gene therapy can potentially be a curative treatment. However, its use and potential to cure WAS are still under investigation.
Prognosis
The prognosis of XLT is good, with the life expectancy close to that of the normal population. However, classic WAS can have a poor prognosis and decreased life expectancy. It can be due to autoimmune disorders, malignancy, or recurrent infections. Bleeding is the most common cause of death in such patients.
Differential Diagnosis
Several syndromes present with eczema and elevated IgE, and susceptibility to infections resemble WAS/XLT. These include:
- Atopic dermatitis
- Hyper IgE syndrome
- Omenn syndrome
- Immune thrombocytopenic purpura
- Congenital neutropenia
Final Remarks
WAS is a rare X-linked disorder seen in males. Diagnosis requires clinical, genetic, and laboratory testing. Its management can be best with an interprofessional team that includes the hematologist, dermatologist, pathologist, geneticist, nursing staff, and pharmacist. Treatment can be conventional and supportive, including the use of prophylactic antibiotics and platelet transfusions to cease the life-threatening hemorrhages. HCT is the only curative treatment available for this condition.
References
[1] Ochs, H.D., et al., Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biology of Blood and Marrow Transplantation, 2009. 15(1): p. 84-90.
[2] Velazquez, F.M.H. and D.M.F. Sarmiento, Caracterización clínico-epidemiológica del Síndrome de Wiskott-Aldrich. EsTuSalud, 2023. 5(1): p. e258-e258.
[3] Blundell MP, Worth A, Bouma G, Thrasher AJ. The Wiskott-Aldrich syndrome: The actin cytoskeleton and immune cell function. Dis Markers. 2010;29(3-4):157-75.
[4] Malinova D, Fritzsche M, Nowosad CR, Armer H, Munro PM, Blundell MP, Charras G, Tolar P, Bouma G, Thrasher AJ. WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts. J Leukoc Biol. 2016 May;99(5):699-710.
[5] Maillard MH, Cotta-de-Almeida V, Takeshima F, Nguyen DD, Michetti P, Nagler C, Bhan AK, Snapper SB. The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med. 2007 Feb 19;204(2):381-91.
[6] Malik, M. A., & Masab, M. (2023). Wiskott-Aldrich syndrome. In StatPearls [Internet]. StatPearls Publishing.
[7] Malik, M. A., & Masab, M. (2023). Wiskott-Aldrich syndrome. In StatPearls [Internet]. StatPearls Publishing.
[8] Gilardin, L., Bayry, J., & Kaveri, S. V. (2015). Intravenous immunoglobulin as clinical immune-modulating therapy. Cmaj, 187(4), 257-264.
[9] Intravenous immune globulin therapy
[10] Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994 Dec;125(6 Pt 1):876-85.