Wiskott-Aldrich syndrome

Genetic MONDO:0010518 Pathograph 23 combined immunodeficiency inherited blood coagulation disorder X-linked disease

Wiskott-Aldrich syndrome is an X-linked primary immunodeficiency caused by pathogenic variants in WAS, which encodes the hematopoietic actin regulator WASp. Loss or dysfunction of WASp disrupts actin cytoskeleton remodeling in leukocytes and platelets, impairing immune-cell migration, antigen-driven activation, immune synapse function, host defense, and platelet production or morphology. The disease is characterized by microthrombocytopenia, bleeding, eczema, recurrent infections, immune dysregulation with autoimmunity and inflammation, and increased risk of lymphoid malignancy.

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1
Mappings
1
Definitions
1
Inheritance
5
Pathophys.
31
Phenotypes
23
Pathograph
1
Genes
4
Treatments
8
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0010518 Wiskott-Aldrich syndrome
skos:exactMatch Orphanet ORPHA:906
Orphanet ORPHA:906 lists MONDO:0010518 as an exact cross-reference for Wiskott-Aldrich syndrome.
📘

Definitions

1
Orphanet Wiskott-Aldrich syndrome definition
A primary immunodeficiency disease with microthrombocytopenia, eczema, infections, and increased risk for autoimmune manifestations and malignancy.
OTHER
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"A primary immunodeficiency disease characterized by microthrombocytopenia, eczema, infections and an increased risk for autoimmune manifestations and malignancies."
Orphanet defines the core immune, platelet, skin, autoimmune, and malignancy features of Wiskott-Aldrich syndrome.
👪

Inheritance

1
X-linked inheritance HP:0001417
Wiskott-Aldrich syndrome is classically inherited as an X-linked disorder caused by pathogenic variants in WAS on the X chromosome.
X-linked inheritance
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"X-linked recessive"
Orphanet records X-linked recessive inheritance for Wiskott-Aldrich syndrome.
PMID:7579347 SUPPORT Human Clinical
"The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
Human molecular analysis describes Wiskott-Aldrich syndrome as X-linked recessive and summarizes the classic clinical phenotype.
⚙

Pathophysiology

5
WAS gene disruption
Pathogenic WAS variants reduce or disrupt WASp, the actin nucleation promoting factor expressed in hematopoietic lineages. This is the upstream molecular lesion for platelet and immune-cell defects.
hematopoietic cell link
Downstream
Actin cytoskeleton signaling defect WASp deficiency disrupts membrane-to-actin cytoskeleton signaling in hematopoietic cells.
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"WAS | WASP actin nucleation promoting factor | hgnc:12731 | Disease-causing germline mutation(s) in"
Orphanet anchors WAS as the disease-causing gene for this disorder.
PMID:7579347 SUPPORT Human Clinical
"These findings provide direct evidence that XLT and WAS are caused"
Human genetic data directly connect WAS mutations to Wiskott-Aldrich syndrome and related X-linked thrombocytopenia.
Actin cytoskeleton signaling defect
WASp normally links receptor and small-GTPase signals to actin filament remodeling. When WASp function is disturbed, hematopoietic cells have defective actin organization, polarization, and motility.
hematopoietic cell link
actin cytoskeleton organization link ↓ DECREASED actin filament organization link ↓ DECREASED
Downstream
Defective immune cell migration and activation Leukocyte actin remodeling defects impair cell migration, antigen uptake, and activation.
Microthrombocytopenia and platelet dysfunction Hematopoietic cytoskeletal dysregulation contributes to small abnormal platelets and bleeding.
Immune dysregulation with autoimmunity and malignancy risk WASp deficiency in regulatory T/B cells and myeloid cells drives immune dysregulation beyond simple immunodeficiency.
Show evidence (2 references)
PMID:10523789 SUPPORT Human Clinical
"of WAS have been shown to be linked to the regulation of the actin cytoskeleton"
Review of human disease mechanisms identifies hematopoietic actin-cytoskeleton regulation as central to WAS pathophysiology.
PMID:10523789 SUPPORT Human Clinical
"transduction of signals from the cell membrane to the actin cytoskeleton."
WASp family proteins are described as connecting membrane signals to actin cytoskeleton regulation.
Defective immune cell migration and activation
WASp-dependent actin remodeling is needed for coordinated immune-cell migration, antigen uptake, immune synapse formation, signaling, and activation. WASp deficiency compromises host defense through these linked cellular defects.
leukocyte link T cell link B cell link
T cell activation link ↓ DECREASED leukocyte mediated immunity link ↓ DECREASED
Downstream
Immunodeficiency Defective leukocyte function produces combined immunodeficiency.
Recurrent respiratory infections Impaired host defense predisposes to recurrent sinopulmonary infections.
Sinusitis Defective host defense contributes to recurrent paranasal sinus infection and inflammation.
Otitis media Defective host defense contributes to recurrent middle-ear infection.
Show evidence (3 references)
PMID:19628299 SUPPORT Human Clinical
"Regulation of the actin cytoskeleton is crucial for many aspects of correct and"
This review links actin regulation to immune-cell functions that are impaired in WAS.
PMID:19628299 SUPPORT Human Clinical
"regulator of actin cytoskeletal rearrangements and lack of this protein results"
WASp deficiency is directly connected to impaired immune function.
PMID:28805251 SUPPORT Other
"including immune synapse formation, cell signaling, migration and cytokine"
Review of human and model data connects WASp to immune synapse formation, signaling, migration, and cytokine release.
Microthrombocytopenia and platelet dysfunction
WAS-related cytoskeletal defects in hematopoietic lineages produce thrombocytopenia with abnormally small or malformed platelets, causing prolonged bleeding and mucocutaneous or internal hemorrhage.
platelet link
actin cytoskeleton organization link ↓ DECREASED
Downstream
Thrombocytopenia Reduced platelet number is the quantitative platelet abnormality.
Abnormal platelet morphology Small or abnormal platelets are the morphologic platelet abnormality.
Prolonged bleeding time Platelet number and morphology defects prolong bleeding.
Bruising susceptibility Platelet defects increase mucocutaneous bruising.
Internal hemorrhage Severe platelet dysfunction can produce clinically significant bleeding.
Show evidence (2 references)
PMID:7579347 SUPPORT Human Clinical
"The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
Human clinical-genetic study identifies thrombocytopenia and small platelets as core WAS manifestations.
PMID:10523789 SUPPORT Human Clinical
"disease characterised by immune dysregulation and microthrombocytopenia."
Review characterizes microthrombocytopenia as a defining manifestation of WAS.
Immune dysregulation with autoimmunity and malignancy risk
Beyond susceptibility to infection, WASp deficiency disrupts regulatory lymphoid and myeloid cell function and B-cell selection, producing autoimmunity, inflammatory complications, and increased malignancy risk.
T cell link B cell link
leukocyte mediated immunity link ⚠ ABNORMAL
Downstream
Autoimmunity Regulatory immune defects predispose to autoimmune manifestations.
Chronic diarrhea Immune dysregulation can manifest as chronic gastrointestinal inflammation and diarrhea.
Lymphoma Immune dysregulation and impaired tumor surveillance increase lymphoid malignancy risk.
Eczematoid dermatitis Immune dysregulation contributes to the eczematoid dermatitis characteristic of WAS.
Show evidence (2 references)
PMID:28805251 SUPPORT Other
"myeloid cells and regulatory T and B cells, as well as defects in positive and"
Mechanistic review links WASp deficiency to defective regulatory immune-cell compartments and B-cell selection.
PMID:26159751 SUPPORT Human Clinical
"associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy"
Clinical treatment review summarizes autoimmunity and malignancy as high-incidence complications.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Wiskott-Aldrich syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

31
Blood 9
Thrombocytopenia VERY_FREQUENT Thrombocytopenia (HP:0001873)
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"HP:0001873 | Thrombocytopenia | Very frequent (99-80%)"
Orphanet records thrombocytopenia as a very frequent WAS phenotype.
PMID:7579347 SUPPORT Human Clinical
"The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
Human molecular study identifies thrombocytopenia as part of the classic WAS phenotype.
Bruising susceptibility VERY_FREQUENT Bruising susceptibility (HP:0000978)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0000978 | Bruising susceptibility | Very frequent (99-80%)"
Orphanet records bruising susceptibility as a very frequent WAS phenotype.
Lymphopenia VERY_FREQUENT Decreased total lymphocyte count (HP:0001888)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0001888 | Lymphopenia | Very frequent (99-80%)"
Orphanet records lymphopenia as a very frequent WAS phenotype.
Petechiae FREQUENT Petechiae (HP:0000967)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0000967 | Petechiae | Frequent (79-30%)"
Orphanet records petechiae as a frequent WAS phenotype.
Purpura FREQUENT Purpura (HP:0000979)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0000979 | Purpura | Frequent (79-30%)"
Orphanet records purpura as a frequent WAS phenotype.
Anemia FREQUENT Anemia (HP:0001903)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0001903 | Anemia | Frequent (79-30%)"
Orphanet records anemia as a frequent WAS phenotype.
Hematochezia FREQUENT Hematochezia (HP:0002573)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0002573 | Hematochezia | Frequent (79-30%)"
Orphanet records hematochezia as a frequent WAS phenotype.
Hemolytic anemia FREQUENT Hemolytic anemia (HP:0001878)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0001878 | Hemolytic anemia | Frequent (79-30%)"
Orphanet records hemolytic anemia as a frequent WAS phenotype.
Lymphoma Lymphoma (HP:0002665)
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"HP:0002665 | Lymphoma | Occasional (29-5%)"
Orphanet records lymphoma as an occasional WAS phenotype.
PMID:26159751 SUPPORT Human Clinical
"associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy"
Clinical review supports increased malignancy risk in WAS.
Cardiovascular 1
Arrhythmia FREQUENT Arrhythmia (HP:0011675)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0011675 | Arrhythmia | Frequent (79-30%)"
Orphanet records arrhythmia as a frequent WAS phenotype.
Digestive 1
Chronic diarrhea VERY_FREQUENT Chronic diarrhea (HP:0002028)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0002028 | Chronic diarrhea | Very frequent (99-80%)"
Orphanet records chronic diarrhea as a very frequent WAS phenotype.
Ear 2
Otitis media VERY_FREQUENT Otitis media (HP:0000388)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0000388 | Otitis media | Very frequent (99-80%)"
Orphanet records otitis media as a very frequent WAS phenotype.
Chronic otitis media VERY_FREQUENT Chronic otitis media (HP:0000389)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0000389 | Chronic otitis media | Very frequent (99-80%)"
Orphanet records chronic otitis media as a very frequent WAS phenotype.
Head and Neck 1
Sinusitis VERY_FREQUENT Sinusitis (HP:0000246)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0000246 | Sinusitis | Very frequent (99-80%)"
Orphanet records sinusitis as a very frequent WAS phenotype.
Immune 4
Immunodeficiency VERY_FREQUENT Immunodeficiency (HP:0002721)
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"HP:0002721 | Immunodeficiency | Very frequent (99-80%)"
Orphanet records immunodeficiency as a very frequent WAS phenotype.
PMID:7579347 SUPPORT Human Clinical
"The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
Human molecular study includes immunodeficiency in the classic clinical description.
Recurrent respiratory infections VERY_FREQUENT Recurrent respiratory infections (HP:0002205)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
Orphanet records recurrent respiratory infections as a very frequent WAS phenotype.
Eczematoid dermatitis Eczematoid dermatitis (HP:0000964)
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"HP:0000964 | Eczematoid dermatitis | Occasional (29-5%)"
Orphanet records eczematoid dermatitis in WAS, and the disorder definition includes eczema.
PMID:7579347 SUPPORT Human Clinical
"The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
Human molecular study identifies eczema as part of the classic WAS phenotype.
Autoimmunity FREQUENT Autoimmunity (HP:0002960)
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"HP:0002960 | Autoimmunity | Frequent (79-30%)"
Orphanet records autoimmunity as a frequent WAS phenotype.
PMID:26159751 SUPPORT Human Clinical
"associated with a bleeding tendency, eczema and a high incidence of autoimmunity"
Clinical review identifies autoimmunity as a high-incidence WAS complication.
Metabolism 1
Fever VERY_FREQUENT Fever (HP:0001945)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0001945 | Fever | Very frequent (99-80%)"
Orphanet records fever as a very frequent WAS phenotype.
Respiratory 2
Chronic pulmonary obstruction VERY_FREQUENT Chronic pulmonary obstruction (HP:0006510)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0006510 | Chronic pulmonary obstruction | Very frequent (99-80%)"
Orphanet records chronic pulmonary obstruction as a very frequent WAS phenotype.
Dyspnea FREQUENT Dyspnea (HP:0002094)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0002094 | Dyspnea | Frequent (79-30%)"
Orphanet records dyspnea as a frequent WAS phenotype.
Constitutional 1
Fatigue FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0012378 | Fatigue | Frequent (79-30%)"
Orphanet records fatigue as a frequent WAS phenotype.
Other 9
Abnormal platelet morphology VERY_FREQUENT Abnormal platelet morphology (HP:0011875)
Show evidence (2 references)
ORPHA:906 SUPPORT Other
"HP:0011875 | Abnormal platelet morphology | Very frequent (99-80%)"
Orphanet records abnormal platelet morphology as a very frequent WAS phenotype.
PMID:7579347 SUPPORT Human Clinical
"The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
The classic human phenotype includes small platelets.
Prolonged bleeding time VERY_FREQUENT Prolonged bleeding time (HP:0003010)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0003010 | Prolonged bleeding time | Very frequent (99-80%)"
Orphanet records prolonged bleeding time as a very frequent WAS phenotype.
Spontaneous hematomas VERY_FREQUENT Spontaneous hematomas (HP:0007420)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0007420 | Spontaneous hematomas | Very frequent (99-80%)"
Orphanet records spontaneous hematomas as a very frequent WAS phenotype.
Internal hemorrhage VERY_FREQUENT Internal hemorrhage (HP:0011029)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0011029 | Internal hemorrhage | Very frequent (99-80%)"
Orphanet records internal hemorrhage as a very frequent WAS phenotype.
Specific learning disability FREQUENT Specific learning disability (HP:0001328)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0001328 | Specific learning disability | Frequent (79-30%)"
Orphanet records specific learning disability as a frequent WAS phenotype.
Abnormality of eosinophils FREQUENT Abnormal eosinophil morphology (HP:0001879)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0001879 | Abnormality of eosinophils | Frequent (79-30%)"
Orphanet records abnormality of eosinophils as a frequent WAS phenotype.
Microcytic anemia FREQUENT Microcytic anemia (HP:0001935)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0001935 | Microcytic anemia | Frequent (79-30%)"
Orphanet records microcytic anemia as a frequent WAS phenotype.
Hematemesis FREQUENT Hematemesis (HP:0002248)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0002248 | Hematemesis | Frequent (79-30%)"
Orphanet records hematemesis as a frequent WAS phenotype.
Large intestine inflammation FREQUENT Inflammation of the large intestine (HP:0002037)
Show evidence (1 reference)
ORPHA:906 SUPPORT Other
"HP:0002037 | Inflammation of the large intestine | Frequent (79-30%)"
Orphanet records inflammation of the large intestine as a frequent WAS phenotype.
🧬

Genetic Associations

1
WAS (Causative)
Show evidence (4 references)
ORPHA:906 SUPPORT Other
"WAS | WASP actin nucleation promoting factor | hgnc:12731 | Disease-causing germline mutation(s) in"
Orphanet identifies WAS as the disease-causing germline gene for Wiskott-Aldrich syndrome.
PMID:7579347 SUPPORT Human Clinical
"12 unique mutations distributed throughout the WAS gene, including insertions,"
Patient-derived molecular data show diverse WAS pathogenic variants in Wiskott-Aldrich syndrome.
PMID:7579347 SUPPORT Human Clinical
"Patients with classic WAS had more"
Genotype-phenotype analysis links truncating or complex variants to the classic severe phenotype.
+ 1 more reference
💊

Treatments

4
Hematopoietic stem cell transplantation
Action: hematopoietic stem cell transplantation MAXO:0000747
Allogeneic hematopoietic stem cell transplantation can correct the hematopoietic immune and platelet compartment and offers curative therapy for severe WAS, especially when performed before advanced complications.
Mechanism Target:
RESTORES WAS gene disruption — Transplantation replaces the affected hematopoietic compartment with donor-derived cells expressing functional WAS.
Show evidence (2 references)
PMID:26159751 SUPPORT Human Clinical
"Stem cell transplantation offers the opportunity of cure for all"
Clinical treatment review supports stem cell transplantation as potentially curative for WAS complications.
PMID:21659547 SUPPORT Human Clinical
"Overall survival was 84.0% and was even higher (89.1% 5-year"
Large retrospective HCT cohort provides human outcome evidence for hematopoietic cell transplantation in WAS.
Gene therapy
Action: gene therapy MAXO:0001001
Autologous gene therapy is an emerging option when a suitable stem cell donor is unavailable or poorly matched, aiming to restore WAS expression in hematopoietic cells while reducing allogeneic transplant toxicity.
Mechanism Target:
RESTORES WAS gene disruption — Gene therapy aims to restore WAS expression in autologous hematopoietic cells.
Show evidence (1 reference)
PMID:26159751 SUPPORT Human Clinical
"therapy trials demonstrate encouraging results and the potential of low-toxicity"
Clinical treatment review supports gene therapy as an emerging option for patients without well-matched stem cell donors.
Supportive management of infections, bleeding, and eczema
Action: supportive care MAXO:0000950
Supportive care before or around definitive therapy includes management of infections, bleeding risk, eczema, autoimmunity, and post-transplant complications.
Target Phenotypes: Immunodeficiency ↗ Thrombocytopenia ↗ Eczema ↗
Show evidence (1 reference)
PMID:26159751 SUPPORT Human Clinical
"management of clinical complications pre- and post-transplant, as well as"
Clinical treatment review supports ongoing management of complications before and after definitive therapy.
Intravenous immunoglobulin prophylaxis
Action: immunoglobulin infusion therapy MAXO:0001480
Intravenous immunoglobulin is used as supportive prophylaxis to reduce infection risk in WAS, especially while patients await or recover from definitive therapy.
Target Phenotypes: Immunodeficiency ↗ Recurrent respiratory infections ↗
Show evidence (1 reference)
PMID:8957959 SUPPORT Human Clinical
"Adequate supportive treatment with IVIG and antibiotic prophylaxis"
Human retrospective cohort supports IVIG with antibiotic prophylaxis as supportive treatment in WAS.
{ }

Source YAML

click to show 
name: Wiskott-Aldrich syndrome
category: Genetic
creation_date: '2026-05-04T03:26:57Z'
updated_date: '2026-05-04T03:26:57Z'
synonyms:
- WAS
- Eczema-thrombocytopenia-immunodeficiency syndrome
description: >
  Wiskott-Aldrich syndrome is an X-linked primary immunodeficiency caused by
  pathogenic variants in WAS, which encodes the hematopoietic actin regulator
  WASp. Loss or dysfunction of WASp disrupts actin cytoskeleton remodeling in
  leukocytes and platelets, impairing immune-cell migration, antigen-driven
  activation, immune synapse function, host defense, and platelet production or
  morphology. The disease is characterized by microthrombocytopenia, bleeding,
  eczema, recurrent infections, immune dysregulation with autoimmunity and
  inflammation, and increased risk of lymphoid malignancy.
disease_term:
  preferred_term: Wiskott-Aldrich syndrome
  term:
    id: MONDO:0010518
    label: Wiskott-Aldrich syndrome
parents:
- combined immunodeficiency
- inherited blood coagulation disorder
- X-linked disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010518
      label: Wiskott-Aldrich syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:906
    mapping_justification: >
      Orphanet ORPHA:906 lists MONDO:0010518 as an exact cross-reference for
      Wiskott-Aldrich syndrome.
external_assertions:
- name: Orphanet Wiskott-Aldrich syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:906
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=906
  description: >
    Orphanet's ORPHA:906 structured record provides exact MONDO and OMIM
    mappings, inheritance categories, definition, epidemiology, disease-gene
    assertion, and HPO phenotype rows used in this curation.
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0010518 | Exact"
    explanation: Orphanet maps ORPHA:906 exactly to the MONDO identifier used here.
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:301000 | Exact"
    explanation: Orphanet maps ORPHA:906 exactly to the classic OMIM Wiskott-Aldrich syndrome record.
definitions:
- name: Orphanet Wiskott-Aldrich syndrome definition
  definition_type: OTHER
  description: >
    A primary immunodeficiency disease with microthrombocytopenia, eczema,
    infections, and increased risk for autoimmune manifestations and malignancy.
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A primary immunodeficiency disease characterized by microthrombocytopenia, eczema, infections and an increased risk for autoimmune manifestations and malignancies."
    explanation: Orphanet defines the core immune, platelet, skin, autoimmune, and malignancy features of Wiskott-Aldrich syndrome.
inheritance:
- name: X-linked inheritance
  description: >
    Wiskott-Aldrich syndrome is classically inherited as an X-linked disorder
    caused by pathogenic variants in WAS on the X chromosome.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "X-linked recessive"
    explanation: Orphanet records X-linked recessive inheritance for Wiskott-Aldrich syndrome.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
    explanation: Human molecular analysis describes Wiskott-Aldrich syndrome as X-linked recessive and summarizes the classic clinical phenotype.
prevalence:
- population: Europe
  percentage: 1-9 per 1,000,000
  notes: Orphanet records European point prevalence in the ultra-rare disease range.
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence | PMID:2012"
    explanation: Orphanet records European point prevalence for Wiskott-Aldrich syndrome.
progression:
- phase: Neonatal or infantile onset
  age_range: Neonatal to infancy
  notes: >
    Platelet abnormalities, bleeding, eczema, and infections typically emerge in
    infancy or the neonatal period, with later complications including
    autoimmunity, inflammatory disease, and malignancy.
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infantile onset for Wiskott-Aldrich syndrome.
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset for Wiskott-Aldrich syndrome.
genetic:
- name: WAS
  gene_term:
    preferred_term: WAS
    term:
      id: hgnc:12731
      label: WAS
  association: Causative
  features: >
    Pathogenic variants across WAS cause a spectrum from classic
    Wiskott-Aldrich syndrome to X-linked thrombocytopenia. More complex
    mutations including termination codons and frameshifts are associated with
    severe classic disease, while some missense alleles cause milder X-linked
    thrombocytopenia.
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WAS | WASP actin nucleation promoting factor | hgnc:12731 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies WAS as the disease-causing germline gene for Wiskott-Aldrich syndrome.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "12 unique mutations distributed throughout the WAS gene, including insertions,"
    explanation: Patient-derived molecular data show diverse WAS pathogenic variants in Wiskott-Aldrich syndrome.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with classic WAS had more"
    explanation: Genotype-phenotype analysis links truncating or complex variants to the classic severe phenotype.
  - reference: CGGV:assertion_a936b3ba-f1d0-4f14-bd56-14f64ad4de3a-2018-10-12T205425.459Z
    reference_title: "WAS / Wiskott-Aldrich syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WAS | HGNC:12731 | Wiskott-Aldrich syndrome | MONDO:0010518 | XL | Definitive"
    explanation: ClinGen classifies the WAS-Wiskott-Aldrich syndrome gene-disease relationship as definitive with X-linked inheritance.
pathophysiology:
- name: WAS gene disruption
  description: >
    Pathogenic WAS variants reduce or disrupt WASp, the actin nucleation
    promoting factor expressed in hematopoietic lineages. This is the upstream
    molecular lesion for platelet and immune-cell defects.
  gene:
    preferred_term: WAS
    modifier: DECREASED
    term:
      id: hgnc:12731
      label: WAS
  cell_types:
  - preferred_term: hematopoietic cell
    term:
      id: CL:0000988
      label: hematopoietic cell
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WAS | WASP actin nucleation promoting factor | hgnc:12731 | Disease-causing germline mutation(s) in"
    explanation: Orphanet anchors WAS as the disease-causing gene for this disorder.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings provide direct evidence that XLT and WAS are caused"
    explanation: Human genetic data directly connect WAS mutations to Wiskott-Aldrich syndrome and related X-linked thrombocytopenia.
  downstream:
  - target: Actin cytoskeleton signaling defect
    description: WASp deficiency disrupts membrane-to-actin cytoskeleton signaling in hematopoietic cells.
- name: Actin cytoskeleton signaling defect
  description: >
    WASp normally links receptor and small-GTPase signals to actin filament
    remodeling. When WASp function is disturbed, hematopoietic cells have
    defective actin organization, polarization, and motility.
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    modifier: DECREASED
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  - preferred_term: actin filament organization
    modifier: DECREASED
    term:
      id: GO:0007015
      label: actin filament organization
  cell_types:
  - preferred_term: hematopoietic cell
    term:
      id: CL:0000988
      label: hematopoietic cell
  evidence:
  - reference: PMID:10523789
    reference_title: "Wiskott-Aldrich syndrome: a disorder of haematopoietic cytoskeletal regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of WAS have been shown to be linked to the regulation of the actin cytoskeleton"
    explanation: Review of human disease mechanisms identifies hematopoietic actin-cytoskeleton regulation as central to WAS pathophysiology.
  - reference: PMID:10523789
    reference_title: "Wiskott-Aldrich syndrome: a disorder of haematopoietic cytoskeletal regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transduction of signals from the cell membrane to the actin cytoskeleton."
    explanation: WASp family proteins are described as connecting membrane signals to actin cytoskeleton regulation.
  downstream:
  - target: Defective immune cell migration and activation
    description: Leukocyte actin remodeling defects impair cell migration, antigen uptake, and activation.
  - target: Microthrombocytopenia and platelet dysfunction
    description: Hematopoietic cytoskeletal dysregulation contributes to small abnormal platelets and bleeding.
  - target: Immune dysregulation with autoimmunity and malignancy risk
    description: WASp deficiency in regulatory T/B cells and myeloid cells drives immune dysregulation beyond simple immunodeficiency.
- name: Defective immune cell migration and activation
  description: >
    WASp-dependent actin remodeling is needed for coordinated immune-cell
    migration, antigen uptake, immune synapse formation, signaling, and
    activation. WASp deficiency compromises host defense through these linked
    cellular defects.
  biological_processes:
  - preferred_term: T cell activation
    modifier: DECREASED
    term:
      id: GO:0042110
      label: T cell activation
  - preferred_term: leukocyte mediated immunity
    modifier: DECREASED
    term:
      id: GO:0002443
      label: leukocyte mediated immunity
  cell_types:
  - preferred_term: leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:19628299
    reference_title: "Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regulation of the actin cytoskeleton is crucial for many aspects of correct and"
    explanation: This review links actin regulation to immune-cell functions that are impaired in WAS.
  - reference: PMID:19628299
    reference_title: "Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regulator of actin cytoskeletal rearrangements and lack of this protein results"
    explanation: WASp deficiency is directly connected to impaired immune function.
  - reference: PMID:28805251
    reference_title: "Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "including immune synapse formation, cell signaling, migration and cytokine"
    explanation: Review of human and model data connects WASp to immune synapse formation, signaling, migration, and cytokine release.
  downstream:
  - target: Immunodeficiency
    description: Defective leukocyte function produces combined immunodeficiency.
  - target: Recurrent respiratory infections
    description: Impaired host defense predisposes to recurrent sinopulmonary infections.
  - target: Sinusitis
    description: Defective host defense contributes to recurrent paranasal sinus infection and inflammation.
  - target: Otitis media
    description: Defective host defense contributes to recurrent middle-ear infection.
- name: Microthrombocytopenia and platelet dysfunction
  description: >
    WAS-related cytoskeletal defects in hematopoietic lineages produce
    thrombocytopenia with abnormally small or malformed platelets, causing
    prolonged bleeding and mucocutaneous or internal hemorrhage.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    modifier: DECREASED
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
    explanation: Human clinical-genetic study identifies thrombocytopenia and small platelets as core WAS manifestations.
  - reference: PMID:10523789
    reference_title: "Wiskott-Aldrich syndrome: a disorder of haematopoietic cytoskeletal regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "disease characterised by immune dysregulation and microthrombocytopenia."
    explanation: Review characterizes microthrombocytopenia as a defining manifestation of WAS.
  downstream:
  - target: Thrombocytopenia
    description: Reduced platelet number is the quantitative platelet abnormality.
  - target: Abnormal platelet morphology
    description: Small or abnormal platelets are the morphologic platelet abnormality.
  - target: Prolonged bleeding time
    description: Platelet number and morphology defects prolong bleeding.
  - target: Bruising susceptibility
    description: Platelet defects increase mucocutaneous bruising.
  - target: Internal hemorrhage
    description: Severe platelet dysfunction can produce clinically significant bleeding.
- name: Immune dysregulation with autoimmunity and malignancy risk
  description: >
    Beyond susceptibility to infection, WASp deficiency disrupts regulatory
    lymphoid and myeloid cell function and B-cell selection, producing
    autoimmunity, inflammatory complications, and increased malignancy risk.
  biological_processes:
  - preferred_term: leukocyte mediated immunity
    modifier: ABNORMAL
    term:
      id: GO:0002443
      label: leukocyte mediated immunity
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:28805251
    reference_title: "Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "myeloid cells and regulatory T and B cells, as well as defects in positive and"
    explanation: Mechanistic review links WASp deficiency to defective regulatory immune-cell compartments and B-cell selection.
  - reference: PMID:26159751
    reference_title: "Current and emerging treatment options for Wiskott-Aldrich syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      associated with a bleeding tendency, eczema and a high incidence of autoimmunity
      and malignancy
    explanation: Clinical treatment review summarizes autoimmunity and malignancy as high-incidence complications.
  downstream:
  - target: Autoimmunity
    description: Regulatory immune defects predispose to autoimmune manifestations.
  - target: Chronic diarrhea
    description: Immune dysregulation can manifest as chronic gastrointestinal inflammation and diarrhea.
  - target: Lymphoma
    description: Immune dysregulation and impaired tumor surveillance increase lymphoid malignancy risk.
  - target: Eczematoid dermatitis
    description: Immune dysregulation contributes to the eczematoid dermatitis characteristic of WAS.
phenotypes:
- category: Clinical
  name: Immunodeficiency
  description: Combined immune dysfunction with susceptibility to recurrent infections.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002721 | Immunodeficiency | Very frequent (99-80%)"
    explanation: Orphanet records immunodeficiency as a very frequent WAS phenotype.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
    explanation: Human molecular study includes immunodeficiency in the classic clinical description.
- category: Clinical
  name: Recurrent respiratory infections
  description: Recurrent sinopulmonary infections are a major consequence of impaired host defense.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
    explanation: Orphanet records recurrent respiratory infections as a very frequent WAS phenotype.
- category: Clinical
  name: Sinusitis
  description: Recurrent or chronic sinus infections are a common upper-airway manifestation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sinusitis
    term:
      id: HP:0000246
      label: Sinusitis
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000246 | Sinusitis | Very frequent (99-80%)"
    explanation: Orphanet records sinusitis as a very frequent WAS phenotype.
- category: Clinical
  name: Otitis media
  description: Middle-ear infections are common in the recurrent infection pattern.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Otitis media
    term:
      id: HP:0000388
      label: Otitis media
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000388 | Otitis media | Very frequent (99-80%)"
    explanation: Orphanet records otitis media as a very frequent WAS phenotype.
- category: Clinical
  name: Chronic otitis media
  description: Persistent middle-ear inflammation or infection can complicate WAS.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Chronic otitis media
    term:
      id: HP:0000389
      label: Chronic otitis media
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000389 | Chronic otitis media | Very frequent (99-80%)"
    explanation: Orphanet records chronic otitis media as a very frequent WAS phenotype.
- category: Clinical
  name: Thrombocytopenia
  description: Reduced platelet count is a defining hematologic manifestation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001873 | Thrombocytopenia | Very frequent (99-80%)"
    explanation: Orphanet records thrombocytopenia as a very frequent WAS phenotype.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
    explanation: Human molecular study identifies thrombocytopenia as part of the classic WAS phenotype.
- category: Clinical
  name: Abnormal platelet morphology
  description: Platelets are characteristically small or otherwise morphologically abnormal.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal platelet morphology
    term:
      id: HP:0011875
      label: Abnormal platelet morphology
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011875 | Abnormal platelet morphology | Very frequent (99-80%)"
    explanation: Orphanet records abnormal platelet morphology as a very frequent WAS phenotype.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
    explanation: The classic human phenotype includes small platelets.
- category: Clinical
  name: Prolonged bleeding time
  description: Platelet number and morphology defects produce prolonged bleeding.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Prolonged bleeding time
    term:
      id: HP:0003010
      label: Prolonged bleeding time
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003010 | Prolonged bleeding time | Very frequent (99-80%)"
    explanation: Orphanet records prolonged bleeding time as a very frequent WAS phenotype.
- category: Clinical
  name: Bruising susceptibility
  description: Easy bruising reflects the bleeding diathesis from platelet abnormalities.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000978 | Bruising susceptibility | Very frequent (99-80%)"
    explanation: Orphanet records bruising susceptibility as a very frequent WAS phenotype.
- category: Clinical
  name: Spontaneous hematomas
  description: Spontaneous hematomas are a severe bleeding manifestation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Spontaneous hematomas
    term:
      id: HP:0007420
      label: Spontaneous hematomas
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007420 | Spontaneous hematomas | Very frequent (99-80%)"
    explanation: Orphanet records spontaneous hematomas as a very frequent WAS phenotype.
- category: Clinical
  name: Internal hemorrhage
  description: Internal bleeding can occur in severe platelet dysfunction.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Internal hemorrhage
    term:
      id: HP:0011029
      label: Internal hemorrhage
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011029 | Internal hemorrhage | Very frequent (99-80%)"
    explanation: Orphanet records internal hemorrhage as a very frequent WAS phenotype.
- category: Clinical
  name: Lymphopenia
  description: Reduced circulating lymphocyte counts reflect immune-system involvement.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001888 | Lymphopenia | Very frequent (99-80%)"
    explanation: Orphanet records lymphopenia as a very frequent WAS phenotype.
- category: Clinical
  name: Fever
  description: Recurrent fever can accompany infection and immune dysregulation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001945 | Fever | Very frequent (99-80%)"
    explanation: Orphanet records fever as a very frequent WAS phenotype.
- category: Clinical
  name: Chronic diarrhea
  description: Chronic diarrhea can reflect immune dysregulation and gastrointestinal inflammation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002028 | Chronic diarrhea | Very frequent (99-80%)"
    explanation: Orphanet records chronic diarrhea as a very frequent WAS phenotype.
- category: Clinical
  name: Chronic pulmonary obstruction
  description: Chronic pulmonary obstructive disease can follow recurrent or chronic lung involvement.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Chronic pulmonary obstruction
    term:
      id: HP:0006510
      label: Chronic pulmonary obstruction
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006510 | Chronic pulmonary obstruction | Very frequent (99-80%)"
    explanation: Orphanet records chronic pulmonary obstruction as a very frequent WAS phenotype.
- category: Clinical
  name: Eczematoid dermatitis
  description: Eczematoid dermatitis is a cardinal skin manifestation of WAS.
  phenotype_term:
    preferred_term: Eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000964 | Eczematoid dermatitis | Occasional (29-5%)"
    explanation: Orphanet records eczematoid dermatitis in WAS, and the disorder definition includes eczema.
  - reference: PMID:7579347
    reference_title: "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder"
    explanation: Human molecular study identifies eczema as part of the classic WAS phenotype.
- category: Clinical
  name: Petechiae
  description: Mucocutaneous bleeding may present as petechiae.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000967 | Petechiae | Frequent (79-30%)"
    explanation: Orphanet records petechiae as a frequent WAS phenotype.
- category: Clinical
  name: Purpura
  description: Mucocutaneous bleeding may present as purpura.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Purpura
    term:
      id: HP:0000979
      label: Purpura
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000979 | Purpura | Frequent (79-30%)"
    explanation: Orphanet records purpura as a frequent WAS phenotype.
- category: Clinical
  name: Specific learning disability
  description: Specific learning disability is recorded as a frequent Orphanet feature in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001328 | Specific learning disability | Frequent (79-30%)"
    explanation: Orphanet records specific learning disability as a frequent WAS phenotype.
- category: Clinical
  name: Abnormality of eosinophils
  description: Abnormal eosinophil morphology is recorded as a frequent Orphanet hematologic feature in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of eosinophils
    term:
      id: HP:0001879
      label: Abnormal eosinophil morphology
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001879 | Abnormality of eosinophils | Frequent (79-30%)"
    explanation: Orphanet records abnormality of eosinophils as a frequent WAS phenotype.
- category: Clinical
  name: Anemia
  description: Anemia is recorded as a frequent Orphanet hematologic manifestation in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001903 | Anemia | Frequent (79-30%)"
    explanation: Orphanet records anemia as a frequent WAS phenotype.
- category: Clinical
  name: Microcytic anemia
  description: Microcytic anemia is recorded as a frequent Orphanet hematologic manifestation in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microcytic anemia
    term:
      id: HP:0001935
      label: Microcytic anemia
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001935 | Microcytic anemia | Frequent (79-30%)"
    explanation: Orphanet records microcytic anemia as a frequent WAS phenotype.
- category: Clinical
  name: Dyspnea
  description: Dyspnea is recorded as a frequent Orphanet respiratory manifestation in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002094 | Dyspnea | Frequent (79-30%)"
    explanation: Orphanet records dyspnea as a frequent WAS phenotype.
- category: Clinical
  name: Hematemesis
  description: Hematemesis is recorded as a frequent Orphanet gastrointestinal bleeding manifestation in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hematemesis
    term:
      id: HP:0002248
      label: Hematemesis
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002248 | Hematemesis | Frequent (79-30%)"
    explanation: Orphanet records hematemesis as a frequent WAS phenotype.
- category: Clinical
  name: Hematochezia
  description: Hematochezia is recorded as a frequent Orphanet gastrointestinal bleeding manifestation in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hematochezia
    term:
      id: HP:0002573
      label: Hematochezia
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002573 | Hematochezia | Frequent (79-30%)"
    explanation: Orphanet records hematochezia as a frequent WAS phenotype.
- category: Clinical
  name: Arrhythmia
  description: Arrhythmia is recorded as a frequent Orphanet cardiovascular feature in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011675 | Arrhythmia | Frequent (79-30%)"
    explanation: Orphanet records arrhythmia as a frequent WAS phenotype.
- category: Clinical
  name: Fatigue
  description: Fatigue is recorded as a frequent Orphanet constitutional feature in WAS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012378 | Fatigue | Frequent (79-30%)"
    explanation: Orphanet records fatigue as a frequent WAS phenotype.
- category: Clinical
  name: Autoimmunity
  description: Autoimmune manifestations are common immune-dysregulation complications.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002960 | Autoimmunity | Frequent (79-30%)"
    explanation: Orphanet records autoimmunity as a frequent WAS phenotype.
  - reference: PMID:26159751
    reference_title: "Current and emerging treatment options for Wiskott-Aldrich syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with a bleeding tendency, eczema and a high incidence of autoimmunity"
    explanation: Clinical review identifies autoimmunity as a high-incidence WAS complication.
- category: Clinical
  name: Hemolytic anemia
  description: Autoimmune or inflammatory hematologic disease may include hemolytic anemia.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001878 | Hemolytic anemia | Frequent (79-30%)"
    explanation: Orphanet records hemolytic anemia as a frequent WAS phenotype.
- category: Clinical
  name: Large intestine inflammation
  description: Colitis-like inflammation can accompany immune dysregulation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Inflammation of the large intestine
    term:
      id: HP:0002037
      label: Inflammation of the large intestine
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002037 | Inflammation of the large intestine | Frequent (79-30%)"
    explanation: Orphanet records inflammation of the large intestine as a frequent WAS phenotype.
- category: Clinical
  name: Lymphoma
  description: Lymphoid malignancy risk is increased in WAS.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: ORPHA:906
    reference_title: "Wiskott-Aldrich syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002665 | Lymphoma | Occasional (29-5%)"
    explanation: Orphanet records lymphoma as an occasional WAS phenotype.
  - reference: PMID:26159751
    reference_title: "Current and emerging treatment options for Wiskott-Aldrich syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      associated with a bleeding tendency, eczema and a high incidence of autoimmunity
      and malignancy
    explanation: Clinical review supports increased malignancy risk in WAS.
treatments:
- name: Hematopoietic stem cell transplantation
  description: >
    Allogeneic hematopoietic stem cell transplantation can correct the
    hematopoietic immune and platelet compartment and offers curative therapy
    for severe WAS, especially when performed before advanced complications.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  target_mechanisms:
  - target: WAS gene disruption
    treatment_effect: RESTORES
    description: Transplantation replaces the affected hematopoietic compartment with donor-derived cells expressing functional WAS.
  evidence:
  - reference: PMID:26159751
    reference_title: "Current and emerging treatment options for Wiskott-Aldrich syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stem cell transplantation offers the opportunity of cure for all"
    explanation: Clinical treatment review supports stem cell transplantation as potentially curative for WAS complications.
  - reference: PMID:21659547
    reference_title: "Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall survival was 84.0% and was even higher (89.1% 5-year"
    explanation: Large retrospective HCT cohort provides human outcome evidence for hematopoietic cell transplantation in WAS.
- name: Gene therapy
  description: >
    Autologous gene therapy is an emerging option when a suitable stem cell
    donor is unavailable or poorly matched, aiming to restore WAS expression in
    hematopoietic cells while reducing allogeneic transplant toxicity.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: WAS gene disruption
    treatment_effect: RESTORES
    description: Gene therapy aims to restore WAS expression in autologous hematopoietic cells.
  evidence:
  - reference: PMID:26159751
    reference_title: "Current and emerging treatment options for Wiskott-Aldrich syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "therapy trials demonstrate encouraging results and the potential of low-toxicity"
    explanation: Clinical treatment review supports gene therapy as an emerging option for patients without well-matched stem cell donors.
- name: Supportive management of infections, bleeding, and eczema
  description: >
    Supportive care before or around definitive therapy includes management of
    infections, bleeding risk, eczema, autoimmunity, and post-transplant
    complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  - preferred_term: Eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:26159751
    reference_title: "Current and emerging treatment options for Wiskott-Aldrich syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "management of clinical complications pre- and post-transplant, as well as"
    explanation: Clinical treatment review supports ongoing management of complications before and after definitive therapy.
- name: Intravenous immunoglobulin prophylaxis
  description: >
    Intravenous immunoglobulin is used as supportive prophylaxis to reduce
    infection risk in WAS, especially while patients await or recover from
    definitive therapy.
  treatment_term:
    preferred_term: immunoglobulin infusion therapy
    term:
      id: MAXO:0001480
      label: immunoglobulin infusion therapy
  target_phenotypes:
  - preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:8957959
    reference_title: "Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adequate supportive treatment with IVIG and antibiotic prophylaxis"
    explanation: Human retrospective cohort supports IVIG with antibiotic prophylaxis as supportive treatment in WAS.
notes: >
  The Orphanet record lists several inheritance categories, but the curated
  inheritance assertion uses the supported classic X-linked WAS gene mechanism.
  ORPHA:906 provides a broad phenotype table; this entry curates all
  very-frequent and frequent Orphanet phenotypes with cached HPO rows, plus
  cardinal eczematoid dermatitis, immune dysregulation, and malignancy
  complications with exact cached snippets.
references:
- reference: ORPHA:906
  title: Wiskott-Aldrich syndrome
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
- reference: PMID:7579347
  title: The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene.
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
- reference: PMID:10523789
  title: "Wiskott-Aldrich syndrome: a disorder of haematopoietic cytoskeletal regulation."
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
- reference: PMID:19628299
  title: "Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation."
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
- reference: PMID:28805251
  title: "Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity."
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
- reference: PMID:26159751
  title: Current and emerging treatment options for Wiskott-Aldrich syndrome.
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
- reference: PMID:21659547
  title: "Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study."
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
- reference: PMID:8957959
  title: "Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome."
  found_in:
  - Wiskott_Aldrich_Syndrome-deep-research-fallback.md
  findings: []
📚

References & Deep Research

References

8
ORPHA:906
Wiskott-Aldrich syndrome
No top-level findings curated for this source.
PMID:7579347
The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene.
No top-level findings curated for this source.
PMID:10523789
Wiskott-Aldrich syndrome: a disorder of haematopoietic cytoskeletal regulation.
No top-level findings curated for this source.
PMID:19628299
Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation.
No top-level findings curated for this source.
PMID:28805251
Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity.
No top-level findings curated for this source.
PMID:26159751
Current and emerging treatment options for Wiskott-Aldrich syndrome.
No top-level findings curated for this source.
PMID:21659547
Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study.
No top-level findings curated for this source.
PMID:8957959
Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome.
No top-level findings curated for this source.

Deep Research

1
Manual Fallback ▸
Wiskott-Aldrich Syndrome Research Fallback

Wiskott-Aldrich Syndrome Research Fallback

Deep-research provider attempts were made after selecting the direct Orphanet/MONDO target ORPHA:906 / MONDO:0010518:

  • timeout 180 just research-disorder falcon Wiskott_Aldrich_Syndrome
  • timeout 180 just research-disorder openai Wiskott_Aldrich_Syndrome
  • timeout 90 just research-disorder openai Wiskott_Aldrich_Syndrome was retried after PR review requested a fresh deep-research attempt.

All provider commands printed the initial provider line, then stalled without producing a completed research output file and were terminated by their timeouts. The curation therefore intentionally used the structured Orphanet cache plus fetched PubMed cache records as the auditable evidence base, with all added phenotype and treatment statements backed by exact snippets from those caches.

Literature Scope Checked

  • references_cache/ORPHA_906.md: direct Orphanet disease record for Wiskott-Aldrich syndrome, including definition, X-linked recessive inheritance, exact MONDO and OMIM mappings, prevalence, age of onset, WAS disease-gene assertion, and HPO phenotype rows.
  • references_cache/PMID_7579347.md: human molecular study showing that Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same WAS gene, with classic WAS linked to complex mutations such as termination codons and frameshifts.
  • references_cache/PMID_10523789.md: review supporting WAS as a disorder of hematopoietic actin-cytoskeleton regulation, including membrane-to-actin signal transduction and defects in cell polarization and motility.
  • references_cache/PMID_19628299.md: review supporting defective immune-cell migration, antigen uptake, activation, and host defense due to WASp deficiency.
  • references_cache/PMID_28805251.md: review supporting WASp roles in innate and adaptive immunity, including immune synapse formation, cell signaling, migration, cytokine release, regulatory T and B cell defects, and B-cell selection abnormalities.
  • references_cache/PMID_26159751.md: clinical treatment review supporting life-threatening disease burden, bleeding tendency, eczema, autoimmunity, malignancy risk, hematopoietic stem cell transplantation, gene therapy, and management of pre- and post-transplant complications.
  • references_cache/PMID_21659547.md: retrospective collaborative human HCT cohort of 194 patients supporting survival outcomes, chimerism, and persistent thrombocytopenia risk when myeloid donor chimerism is low.
  • references_cache/PMID_8957959.md: retrospective human supportive-care series directly supporting IVIG with antibiotic prophylaxis in Wiskott-Aldrich syndrome.

Curation Conclusions

  • Disease identity is the syndrome-level disorder ORPHA:906, exact to MONDO:0010518 and OMIM:301000.
  • The primary mechanism is WAS pathogenic variation causing deficient or dysfunctional WASp in hematopoietic cells.
  • WASp dysfunction disrupts actin cytoskeleton organization and membrane-to- actin signaling, producing impaired immune-cell migration, antigen uptake, activation, immune synapse function, signaling, cytokine release, and host defense.
  • Platelet involvement is represented as microthrombocytopenia with abnormal platelet morphology, prolonged bleeding time, bruising, hematomas, and internal hemorrhage.
  • Orphanet directly supports the curated very-frequent phenotypes: immunodeficiency, recurrent respiratory infections, sinusitis, otitis media, chronic otitis media, thrombocytopenia, abnormal platelet morphology, prolonged bleeding time, bruising susceptibility, spontaneous hematomas, internal hemorrhage, decreased total lymphocyte count, fever, chronic diarrhea, and chronic pulmonary obstruction.
  • Orphanet also directly supports all curated frequent phenotypes in the cached ORPHA:906 table: petechiae, purpura, specific learning disability, hemolytic anemia, abnormality of eosinophils, anemia, microcytic anemia, inflammation of the large intestine, dyspnea, hematemesis, hematochezia, autoimmunity, arrhythmia, and fatigue.
  • Additional evidence-backed features include eczematoid dermatitis and lymphoma.
  • Evidence-backed treatments are hematopoietic stem cell transplantation, emerging gene therapy, supportive management of infections, bleeding, eczema, autoimmunity, and transplant-related complications, and IVIG prophylaxis.