Hematology

Primary immunodeficiency disorders

Wiskott-Aldrich syndrome



Topic Completed: 6 July 2021

Minor changes: 6 July 2021

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PubMed Search: Wiskott-Aldrich syndrome

Jinjun Cheng, M.D., Ph.D.
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Cite this page: Cheng J. Wiskott-Aldrich syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/spleenwiskott.html. Accessed December 8th, 2021.
Definition / general
  • X linked primary immunodeficiency disorder with the following classic presentation: thrombocytopenia with abnormal bleeding, eczema and recurrent infections
Essential features
Terminology
  • Wiskott-Aldrich syndrome, X linked thrombocytopenia (XLT), X linked neutropenia (XLN), all known as WAS related disorders
ICD coding
  • ICD-10: D82.0 - Wiskott-Aldrich syndrome
Epidemiology
  • 1 - 4 per 1,000,000 live male births
Pathophysiology
  • WASP protein structure:
    • WASP gene encodes a 502 amino acid protein expressed exclusively in the cytoplasm of hematopoietic cells
    • C terminal tripartite domain of WASP contains a common actin monomer binding motif, the verprolin homology domain (V) and a central acidic region (A) that is capable of activating the actin related protein (Arp)2/3 complex, a potent nucleator of actin polymerization (Annu Rev Cell Dev Biol 2002;18:247)
      • A proline rich region in exon 10 required for optimal actin polymerization activity has been shown to be indispensable for effective recruitment of WASP to the immunologic synapse in T cells (Immunity 2003;18:141)
    • N terminal region of WASP allows recruitment of the WASP interacting protein (WIP); in resting lymphocytes, WASP constitutively associates with WIP, stabilizing the inactive conformation of WASP (Mol Cell 2002;10:1269)
    • Following interaction with the T cell antigen receptor, WIP is phosphorylated, resulting in disengagement of WASP from the WIP / WASP complex, thus allowing WASP activation by Cdc42, which leads to actin polymerization and stabilization of actin filaments (Cell 2002;111:565)
  • WASP mutation spectrum:
    • Total of 141 unique WASP mutations were detected in 262 patients; the most common WAS mutations were missense mutations (35.3%), followed by splice site mutations (19.4%), deletions (17.6%) and nonsense mutations (15.4%); insertions and complex mutations made up less than 13% of the mutations identified (Blood 2004;104:4010)
    • Missense mutants that cause the immune disorder Wiskott-Aldrich syndrome (WAS) map primarily to the enabled / VASP homology 1 (EVH1) domain of the actin regulatory protein WASP; more than 300 such mutations have been described (Ann Diagn Pathol 2019;43:151413)
  • Functional mechanisms:
    • Affects functions of both T and B cells
    • WAS mutants can cause a downregulation of T cell receptor signaling through reduced stability of the immune synapse following its formation, which may result in failure of immune activation (Immunology 2010;131:466, Haematologica 2011;96:1415)
    • Besides the WASP regulation of the cytoskeleton dependent immune synapse formation, the interaction between the translocation of the transcription factor of nuclear factor of activated T cells (NFAT) and the Ena-VASP homology domain (EVH1) of WASP, prevents Th1 cytokines secretion from the CD4+ cells, while increasing the relative amount of Th2 cytokines (J Exp Med 2018;215:1009, Ann Diagn Pathol 2019;43:151413)
Clinical features
  • Thrombocytopenia and very small platelets usually present at birth (Blood 2004;103:456)
  • Life threatening bleeding (occurs in 30% of males prior to diagnosis; sites including brain, gastrointestinal tract)
  • Skin eczema in 80% of the cases; other skin lesions include impetigo, cellulitis and abscesses
  • Increased risk of infections, mostly recurrent ear infections and some viruses such as cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV)
  • Increased risk of autoimmune disorders that may include hemolytic anemia, immune thrombocytopenic purpura, rheumatoid arthritis, vasculitis of small and large vessels and immune mediated damage to the kidneys and liver
  • Increased risk of developing cancer, such as lymphoma, especially in setting of EBV infection or older patients with autoimmune disease; high risk for EBV+ non-Hodgkin lymphoma and other malignancies (leukemia, myelodysplastic syndrome, solid tumor) at mean age of 9.5 years (Blood 2009;113:6288)
  • Isolated EBV lymphoproliferative disease resembling cutaneous lymphomatoid granulomatosis was reported in a child with Wiskott-Aldrich syndrome (J Clin Pathol 2003;56:555, Clin Immunol Immunopathol 1986;41:479)
  • Vaccination often ineffective due to body’s inability to mount normal protective antibody response
Diagnosis
Laboratory
  • Complete blood count shows anemia, eosinophilia, microthrombocytopenia; determining platelet size and shape in a boy with thrombocytopenia is a rapid diagnostic clue (Curr Opin Hematol 2008;15:30)
  • Patients typically have elevated levels of IgE and IgA, sometimes with low levels of IgM; the T cell function is often abnormal, such as T cell lymphopenia, abnormal response to mitogen or impaired antibody production (J Clin Immunol 2018;38:13)
  • WAS is well known to have associated peripheral eosinophilia, induced by cytokines such as IL4 and IL5 (Ann Diagn Pathol 2019;43:151413)
Case reports
Treatment
  • Treatment for Wiskott-Aldrich syndrome is based on a person’s clinical condition; possible treatment options include immunoglobulin (antibody) infusions, platelet transfusions, topical creams for eczema, steroids or similar medications to control autoimmunity
  • Stem cell transplant: allogeneic HCT for WAS has been a standard curative therapy to be considered immediately at the time of diagnosis; patients undergoing sibling matched transplant can achieve great survival rate (Lancet 2003;361:553, Immunol Allergy Clin North Am 2010;30:179)
  • Splenectomy: improves platelet counts, platelet size normalizes; potential need for prophylactic antibiotics given further increase in risk of infection / sepsis and death; splenectomy may be reserved only for patients who are unlikely to ever be transplanted (Immunol Allergy Clin North Am 2010;30:179, N Engl J Med 1980;302:892)
  • Gene therapy clinical trial ongoing (Boston Children's Hospital: Wiskott-Aldrich Syndrome [Accessed 6 July 2021])
    • Based on transplanting genetically modified stem cells from the patient's own bone marrow or blood
Microscopic (histologic) description
  • Spleen in Wiskott-Aldrich syndrome (WAS) patients shows:
    • Significant depletion of the white pulp, affecting both T and B cell areas
    • Splenic marginal zone in patients with WAS is severely depleted
    • Follicles are heterogeneous in morphologic appearance
    • Red pulp plasma cells in WAS patients are similar to those in control subjects (Am J Surg Pathol 1999;23:182)
  • Lymph node biopsy shows preserved architecture with prominent reactive follicles and eosinophils in paracortex; however, the reduction in germinal center has been confirmed in WAS protein deficient murine model (Cell Immunol 2019;341:103919)
Peripheral smear description
  • Peripheral blood smear shows thrombocytopenia with small platelets and eosinophilia; lymphopenia is characteristic for classic WAS during childhood (Blood 2004;104:4010)
Flow cytometry description
Molecular / cytogenetics description
Differential diagnosis
  • Deficiency of WAS protein interacting protein (WIP deficiency) causes an autosomal recessive, WAS-like syndrome with early onset combined immunodeficiency that has been described in few pedigrees (Front Immunol 2018;9:2554, J Leukoc Biol 2014;96:713, J Exp Med 2012;209:29)
  • Mutation analysis alone is of limited value in predicting the clinical phenotype; the vast majority of XLT patients carry missense mutations in exons 1 and 2 of the WAS gene (Blood 2004;104:4010)
  • Missense mutations in the GTP-ase binding domain (GBD) or Cdc42 binding domain of WAS result in constitutive activation of the protein, causing X linked neutropenia (XLN), with neither thrombocytopenia nor signs of T cell immunodeficiency (Blood 2006;108:2182, Br J Haematol 2009;144:120, Nat Genet 2001;27:313)
  • CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 cosignaling of T cells; homozygous mutation of the CARMIL2 gene, like decreased WASP, dysregulates cell to cell signaling by actin dysregulation; patients present with dermatitis, esophagitis, recurrent skin and chest infections, as well as an increased risk for EBV associated smooth muscle tumors (Front Immunol 2018;9:203)
  • DOCK8 is linked to WASP through the WASP interacting protein (WIP), which also stabilizes WASP from degradation and itself can result in a primary immune deficiency syndrome identical to WAS when deficient (Front Immunol 2021;11:604206, Clin Immunol 2017;181:75)
Board review style question #1
A postnatal day 12 male infant presented with thrombocytopenia. Cardiopulmonary and abdomen examination showed no obvious abnormalities. Results of blood tests before admission were as follows: white blood cell 9.7 x 109/L, hemoglobin 156 g/L, platelet 50 x 109/L, neutrophil 58%, lymphocyte 25%. The immune function examination and blood lymphocyte subsets tests were mildly abnormal. The child died from brain bleeding shortly after admission. The family history documented that the infant’s uncle died in infancy due to repeated infections. His mother was physically healthy. A panel of gene mutation studies was performed and a loss of function mutation was detected in one of the genes. Which of the following genes is the most likely mutated in this child?

  1. CXCR4
  2. FAS
  3. IL7R
  4. RAG1/2
  5. WASP
Board review style answer #1
E. WASP gene

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