Definition/General
Introduction:
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by the classical triad of microthrombocytopenia, eczema, and recurrent infections
It results from mutations in the WAS gene encoding WASP (Wiskott-Aldrich syndrome protein)
The syndrome shows variable clinical severity.
Origin:
Results from mutations in WAS gene on X chromosome (Xp11.23)
The gene encodes WASP protein involved in actin cytoskeleton regulation
Loss-of-function mutations cause classical WAS
Gain-of-function mutations cause X-linked neutropenia
Affects multiple hematopoietic lineages.
Classification:
Classified by clinical severity: Classical WAS (complete triad)
X-linked thrombocytopenia (XLT, milder form)
X-linked neutropenia (XLN, gain-of-function)
Severe WAS (early autoimmunity)
Mild WAS (isolated thrombocytopenia).
Epidemiology:
Rare disorder with incidence 1-4 per million male births
X-linked inheritance affects males primarily
Carrier females may show mild features
Variable expressivity within families
Higher prevalence in certain populations.
Clinical Features
Presentation:
Microthrombocytopenia (small platelets, low count)
Eczematous dermatitis (severe, chronic)
Recurrent infections (bacterial, viral, fungal)
Autoimmune manifestations
Increased malignancy risk
Bleeding tendency.
Symptoms:
Easy bruising and petechiae
Severe eczema from infancy
Recurrent sinopulmonary infections
Bloody diarrhea
Autoimmune cytopenias
Lymphoma development
Poor wound healing.
Risk Factors:
X-linked inheritance (maternal transmission)
Family history of immunodeficiency
Male gender
Carrier mother
Previous affected male siblings
No environmental risk factors.
Screening:
Complete blood count (microthrombocytopenia)
Platelet size analysis
Immunoglobulin levels
T and B cell enumeration
WASP protein expression
Genetic testing for WAS mutations.
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Gross Description
Appearance:
Bone marrow aspirate shows normal cellularity
Normal or increased megakaryocytes
Small, dysplastic megakaryocytes may be present
Normal erythropoiesis and granulopoiesis
Possible lymphoid aggregates.
Characteristics:
Normocellular bone marrow
Adequate megakaryocyte numbers
Possible megakaryocyte morphological abnormalities
Normal other lineages
Reactive lymphoid elements may be present.
Size Location:
Normal bone marrow distribution
Lymph nodes enlarged (reactive)
Splenomegaly common
No focal bone marrow lesions
Systemic lymphadenopathy.
Multifocality:
Uniform bone marrow pattern
Systemic immune dysfunction
Progressive deterioration
Malignancy development risk
Multi-organ involvement.
Microscopic Description
Histological Features:
Normal bone marrow cellularity
Normal or increased megakaryocytes
Small megakaryocytes with abnormal morphology
Normal erythropoiesis
Normal granulopoiesis
Reactive lymphoid elements.
Cellular Characteristics:
Micromegakaryocytes (small size)
Hypolobated nuclei in megakaryocytes
Reduced platelet production
Normal other cell morphology
Lymphoid reactivity
No dysplastic changes in other lineages.
Architectural Patterns:
Preserved bone marrow architecture
Appropriate cellular distribution
Possible lymphoid aggregates
Normal sinusoidal pattern
No fibrosis
Reactive changes.
Grading Criteria:
Severity by clinical score: Severe (classical triad + autoimmunity)
Moderate (classical triad)
Mild (XLT phenotype)
Platelet size consistently small
WASP expression reduced/absent.
Immunohistochemistry
Positive Markers:
CD61 and CD41 highlight megakaryocytes
CD3 and CD20 show lymphoid elements
CD68 marks macrophages
Glycophorin A shows erythropoiesis
MPO highlights granulopoiesis.
Negative Markers:
WASP protein reduced or absent (key finding)
Viral markers variable
Blast markers negative initially
Abnormal infiltrates initially negative.
Diagnostic Utility:
Demonstrates WASP protein deficiency
Confirms megakaryocyte presence
Shows lymphoid reactivity
Assesses immune cell populations
Monitors malignant transformation
Guides therapy decisions.
Molecular Subtypes:
Classical WAS (absent WASP)
XLT variant (reduced WASP)
XLN variant (gain-of-function)
Different mutation types
Genotype-phenotype correlations.
Molecular/Genetic
Genetic Mutations:
WAS gene mutations (Xp11.23)
Missense mutations (milder phenotype)
Nonsense mutations (severe phenotype)
Deletion mutations (severe phenotype)
Splice site mutations
Over 300 mutations described.
Molecular Markers:
Absent or reduced WASP protein
Defective actin polymerization
Abnormal platelet function
Immune cell dysfunction
Increased apoptosis
Genomic instability.
Prognostic Significance:
Severe mutations worse prognosis
Early autoimmunity poor outcome
Malignancy development (EBV-associated lymphomas)
Bone marrow transplant curative
Gene therapy promising
Without treatment fatal.
Therapeutic Targets:
Bone marrow transplantation (curative)
Gene therapy (experimental success)
Immunoglobulin replacement
Platelet transfusions
Immunosuppression for autoimmunity
Antimicrobial prophylaxis.
Differential Diagnosis
Similar Entities:
Immune thrombocytopenic purpura
Other primary immunodeficiencies
Bernard-Soulier syndrome
X-linked thrombocytopenia
Autoimmune lymphoproliferative syndrome
Severe combined immunodeficiency.
Distinguishing Features:
WAS: Small platelets (pathognomonic)
WAS: Eczema and infections
WAS: WASP deficiency
ITP: Normal platelet size
ITP: No immunodeficiency
BSS: Giant platelets
XLT: Milder phenotype
XLT: Preserved WASP function.
Diagnostic Challenges:
Recognizing microthrombocytopenia
Confirming WASP deficiency
Distinguishing from XLT variant
Carrier detection
Prenatal diagnosis
Treatment timing.
Rare Variants:
Atypical WAS without full triad
Late-onset WAS
WAS with isolated autoimmunity
Female WAS (X-inactivation)
Somatic reversion.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Wiskott-Aldrich Syndrome
Classification
Classification: X-linked immunodeficiency with thrombocytopenia
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with megakaryocytic abnormalities
Lineage Assessment
Megakaryopoiesis: present but morphologically abnormal (small cells). Erythropoiesis: normal. Granulopoiesis: normal
Morphological Features
Shows small megakaryocytes with hypolobated nuclei and reduced platelet production
Special Studies
WASP protein: [reduced/absent]
Genetic testing: recommend WAS gene analysis
Clinical correlation: microthrombocytopenia, eczema, infections
Clinical Correlation
Findings consistent with Wiskott-Aldrich syndrome. Recommend genetic counseling
Final Diagnosis
Bone marrow showing changes consistent with Wiskott-Aldrich syndrome