Basics
Description
- An X-linked primary immunodeficiency caused by a mutation in the Wiskott-Aldrich syndrome (WAS) gene
- Originally described as clinical triad of thrombocytopenia with small platelets, eczema, and recurrent infections with opportunistic and pyogenic organisms
- Increased bleeding tendency secondary to thrombocytopenia likely results from impaired platelet production, increased turnover, and defective function.
- Disease variants also resulting from WAS gene mutations include X-linked thrombocytopenia (XLT) and X-linked neutropenia (XLN).
- Classic WAS is characterized by broad immunodeficiency, decreased number and function of T cells, disturbed marginal B-cell homeostasis, and skewed immunoglobulin isotypes, with defective antibody responses to vaccinations, impaired NK-cell cytotoxicity, and abnormal regulatory T-cell function as well as reduced phagocyte chemotaxis.
Epidemiology
- Presents in infancy with serious bleeding episodes secondary to thrombocytopenia (such as circumcision with increased bleeding, bloody diarrhea, ecchymoses)
- Recurrent infections usually start after 6 months of age:
- Bacterial: otitis media, sinusitis, meningitis, sepsis, and pneumonia
- Viral infections: herpes simplex virus, varicella with systemic complications
- Milder phenotypes may lack history of recurrent infections.
- Decline in T- and B-cell numbers with time
- Eczema is usually present by 1 year of age (may be resistant to therapy, sometimes requiring systemic antibiotics).
Incidence
- For WAS/XLT, estimate is 10 in 1 million live births.
- Prevalence of XLT equal to WAS
Risk Factors
Genetics
- X-linked recessive disease
- Defective Wiskott-Aldrich syndrome protein gene located on X p11.22p " 11.23
- ’ Ό60% of cases will have a positive family history for WAS.
- XLT without the other findings is caused by mutations of the same gene.
- Genotype/phenotype correlation
- Lack of Wiskott-Aldrich syndrome protein (WASP) expression: increased infections, severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies
- Survival rate significantly lower in WASP-negative patients
Etiology
- Mutations in the gene for the WASP
- WASP is involved in the reorganization of the actin cytoskeleton in hematopoietic cells:
- Following activation of WASP, reorganization of actin cytoskeleton results in polarization of cells (e.g., polarized actin mesh in platelets for clotting and in macrophages for phagocytosis, and polarization of T or B cells to form immunologic synapses).
- WASP is a cytoplasmic protein involved in cell mobility, immune regulation, cell signaling, cell-to-cell interactions, signaling, and cytotoxicity.
- Defects in WASP can lead to dysfunction in adaptive and innate immunity, immune surveillance, and platelet homeostasis and function as well as neutropenia.
- "Classic " WAS and XLT result from loss-of-function mutations.
- XLT can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP) that does not carry increased risk of malignancy, so testing for WASP expression and WAS gene mutation is important in any male with thrombocytopenia and small platelets.
- XLN results from "activating " mutations in WAS that lead to increased actin polymerization; profound neutropenia, with or without associated lymphopenia; decreased T-cell proliferation in vitro; and increased risk of myelodysplastic changes in bone marrow.
- WASP is also important for regulatory T-cell function.
Commonly Associated Conditions
Associated with IgA nephropathy, autoimmune disorders, and an increased incidence of B-cell lymphomas
Diagnosis
- Diagnosis should be considered in any boy who has congenital or early-onset thrombocytopenia with small platelets.
- Definitive diagnosis
- Male patient
- Congenital thrombocytopenia (<70,000/mm3)
- Small platelets (mean platelet volume <0.5 fL)
- Mutation in the WASP gene or absent WASP mRNA
History
- Persistent or severe bleeding in infancy due to thrombocytopenia
- Recurrent infections, especially by bacteria with capsular polysaccharides (e.g., pneumococcus)
- Eczema can be of variable severity:
- "Acute or chronic "
- 80% of cases associated with eczema
- May result from imbalance of cytokines skewed toward Th2
- Older patients may report recurrent viral infections.
- Most common autoimmune features include autoimmune hemolytic anemia, cutaneous vasculitis, arthritis, and nephropathy.
- Less common autoimmune features include inflammatory bowel disease, ITP, and neutropenia.
- Autoimmune features are poor prognostic indicators and can occur simultaneously.
- Maternal family history of WAS or XLT
Physical Exam
- Evaluation should focus on presence of infection.
- Dermatologic examination is significant for the extent of eczema and the presence of petechiae or ecchymoses.
- Splenomegaly
Diagnostic Tests & Interpretation
Lab
- CBC with differential
- Small platelets, decreased mean platelet volume, decreased platelet count
- Normal IgG, decreased IgM, increased IgA and IgE (reflecting immune dysregulation)
- Reduced or absent responses to polysaccharide antigens and isohemagglutinins to ABO antigens
- T- and B-lymphocyte enumeration and mitogen stimulation studies may progressively deteriorate with increasing age.
Diagnostic Procedures/Other
- WAS disease scoring system useful for defining clinical phenotypes associated with WAS mutations (XLN, XLT vs. classic WAS)
- Sequencing of WAS gene
- Lymph node biopsy in suspected malignancy
- Bone marrow aspirate to evaluate thrombocytopenia
Differential Diagnosis
- Other causes of thrombocytopenia such as ITP
- In 1 cohort, approximately 7% of patients diagnosed as having ITP actually had WAS as an underlying cause of thrombocytopenia.
- Severe atopic disease with dermatitis and secondary skin infections
- HIV infection
- Hyper-IgE syndrome
Treatment
General Measures
- Antibiotics for acute infections and prophylactically in postsplenectomy patients
- Splenectomy may be helpful for persistent severe thrombocytopenia in select patients. However, this may greatly increase the risk of overwhelming infections with encapsulated organisms.
- Splenectomy should be reserved for emergencies in classic WAS patients who are candidates for hematopoietic stem cell transplantation (HSCT) because it is a risk factor for death. Splenectomy in XLT with severe bleeding may increase platelet counts, but risk of severe infection requires lifelong antibiotic prophylaxis.
- Thrombocytopenia precautions: No aspirin and avoidance of situations in which trauma (especially head trauma) is likely to occur, such as contact sports.
- Platelet transfusions may be necessary for severe bleeding. Use irradiated blood products to avoid graft versus host disease and cytomegalovirus-negative products in case of bone marrow transplantation.
- Immunoglobulin replacement therapy is helpful in managing recurrent infections in some patients:
- HSCT is the treatment of choice for the classic WAS phenotype.
- Allogeneic stem cell transplant from human leukocyte antigen (HLA) genotypically identical sibling or 9/10 or 10/10 allele matched unrelated donor for any WAS patient with disease score 3 " 5 (see "Additional Reading " ) or with absent WASP expression
- Outcomes are improving with 5-year survival rates >80% for matched sibling donors and similar for matched unrelated donor grafts <5 years of age. Transplant outcomes for patients >5 years of age with matched sibling or matched unrelated are also improving over time.
- Consider food allergy as exacerbating factor for eczema.
- First retroviral-based gene therapy trial in WAS recently completed in Germany with good immune reconstitution and increase in platelet counts in 9/10 patients. Lentiviral-based gene therapy trials are starting in the near future.
- XLT patients have excellent long-term survival with supportive treatment, but HLA-matched sibling transplant can be considered owing to morbidity.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Signs and symptoms of malignancy should be evaluated expeditiously.
- As patients age, a progressive increase in infectious and autoimmune complications may occur.
Complications
- Progressive decline in immunologic function with an increase in infections. Humoral and cellular immune systems are affected.
- Increased frequency of autoimmune phenomena such as arthritis and vasculitis. The most common is hemolytic anemia. Vasculitis, Henoch-Sch Άnlein purpura, inflammatory polyarthritis, and inflammatory bowel disease are also observed.
- ’ Ό100-fold increased risk of malignancy compared with the general pediatric population. Malignancy is more common in adolescents. Associated with Epstein-Barr virus
- Bleeding episodes can be life threatening.
- Immune reconstitution via stem cell transplant or gene therapy needed to prevent autoimmune disorders, lymphoma, and other malignancy
- Success of bone marrow transplant in last 10 years significantly improved.
- Splenectomy not recommended for classic WAS but may have role in XLT.
Additional Reading
- Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol. 2011;18(1):42 " 48. [View Abstract]
- Auiti A, Biasco L, Scaramuzza S, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151. [View Abstract]
- Binder V, Albert M, Kabus M, et al. The genotype of the original Wiskott phenotype. N Engl J Med. 2006;355(17):1790 " 1793. [View Abstract]
- Bosticardo M, Marangoni F, Aiuti A, et al. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood. 2009;113(25):6288 " 6295. [View Abstract]
- Bryant N, Watts R. Thrombocytopenic syndromes masquerading as childhood immune thrombocytopenic purpura. Clin Pediatr. 2011; 50(3):225 " 230. [View Abstract]
- Charrier S, Dupre L, Scaramuzza S, et al. Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients. Gene Ther. 2007;14(5):415 " 428. [View Abstract]
- Imai K, Morio T, Zhu Y, et al. Clinical course of patients with WASP gene mutations. Blood. 2004;103(2):456 " 464. [View Abstract]
- Jin Y, Mazza C, Christie J, et al. Mutations of the Wiskott-Aldrich syndrome protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004;104(13):4010 " 4019. [View Abstract]
- Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285:26 " 43. [View Abstract]
- Ochs HD. The Wiskott-Aldrich syndrome. Clin Rev Allergy Immunol. 2001;20(1):61 " 86. [View Abstract]
- Schurman SH, Candotti F. Autoimmunity in Wiskott-Aldrich syndrome. Curr Opin Rheumatol. 2003;15(4):446 " 453. [View Abstract]
- Shcherbina A, Candotti F, Rosen F, et al. High incidence of lymphomas in a subgroup of Wiskott-Aldrich syndrome patients. Br J Haematol. 2003;121(3):529 " 530. [View Abstract]
- Simon KL, Anderson SM, Garabedian EK, et al. Molecular and phenotypic abnormalities of B lymphocytes in patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2014;133(3):896 " 9.e4 [View Abstract]
Codes
ICD09
- 279.12 Wiskott-aldrich syndrome
ICD10
- D82.0 Wiskott-Aldrich syndrome
SNOMED
- 36070007 Wiskott-Aldrich syndrome (disorder)
FAQ
- Q: What is the life expectancy for patients with Wiskott-Aldrich syndrome?
- A: Before currently available therapies, most affected patients died in childhood. Currently, many patients live into their 3rd and 4th decades, even without bone marrow transplantation. Major causes of mortality are infections (44%), bleeding (23%), and malignancies (26%). Incidence of malignancy increases in 3rd decade of life. Successfully transplanted patients have a prolonged life expectancy. Patients with no gene expression have a poorer outcome.
- Q: Should patients with Wiskott-Aldrich syndrome receive live viral vaccines?
- A: These vaccines should be avoided because of the variable cellular immune defects associated with Wiskott-Aldrich syndrome. In general, patients receiving IV immunoglobulin do not require vaccinations.
- Q: What is the chance of a sibling having Wiskott-Aldrich syndrome?
- A: As with any X-linked disease, there is a 50% chance of another affected male child or asymptomatic carrier female. Genetic counseling should be offered to carrier females.
- Q: Can Wiskott-Aldrich syndrome be diagnosed prenatally?
- A: In families with affected males, fetal blood sampling can be performed in male fetuses to assess the size of the platelets. Small platelet size and family history of Wiskott-Aldrich syndrome suggest an affected infant.