Wiskott-Aldrich syndrome is an X-linked recessive immunodeficiency presenting in infant boys with the classic triad of thrombocytopenia with small platelets, eczema, and recurrent infections due to combined B- and T-cell dysfunction.

Wiskott-Aldrich Syndrome (WAS) — Paediatric Primary Immunodeficiency

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency (PID) / inborn error of immunity caused by loss-of-function mutations in the WAS gene (Xp11.22–p11.23), which encodes the Wiskott-Aldrich syndrome protein (WASp).

Let's break down the name:

Wiskott — Dr Alfred Wiskott (1937, Germany) described three brothers with thrombocytopenia, bloody diarrhoea, and eczema.
Aldrich — Dr Robert Aldrich (1954, USA) identified the X-linked inheritance pattern in a Dutch-American family.

WASp is a key intracellular signalling protein expressed exclusively in haematopoietic cells. It is critical for actin cytoskeleton remodelling, which is essential for cell migration, cell signalling, immune synapse formation, and platelet function. When WASp is absent or dysfunctional, essentially every arm of the immune system is impaired to some degree, and platelets are both reduced in number and abnormally small.

The classical clinical triad is: immunodeficiency + microthrombocytopenia + eczema. ^[1]^[2]

More completely, as emphasised in the GC lecture and senior notes:

The tetrad of WAS is: eczema, microthrombocytopenia (platelets that are both low AND small), immunodeficiency, and bloody diarrhoea (secondary to thrombocytopenia). ^[2]

High Yield – The WAS Tetrad

The classic triad (eczema + thrombocytopenia + immunodeficiency) is most commonly tested. However, Jerry's immunodeficiencies notes and the Block C paediatric lecture explicitly list a tetrad that adds bloody diarrhoea (a consequence of microthrombocytopenia causing GI bleeding). Know both formulations for exams.

2. Epidemiology

Incidence: approximately 1–10 per 1,000,000 live male births worldwide ^[3].
Accounts for roughly 1–2% of all primary immunodeficiencies in international registries.
Within the IUIS 2022 classification, WAS falls under "Combined immunodeficiencies with associated or syndromic features" (Category 2), which collectively constitute about 15.2% of all PIDs ^[1].

Males almost exclusively affected (X-linked recessive). Females are typically carriers.
- Rare exceptions: females can be affected if they have skewed X-inactivation, homozygous mutations (extremely rare), or Turner syndrome (45,X) with a WAS mutation on the single X.
No racial or ethnic predilection — reported worldwide, including in Hong Kong Chinese families.
Median age at diagnosis: typically within the first year of life — many present in the neonatal period or early infancy with petechiae, bloody stools, or eczema.

WAS is a recognised diagnosis in Hong Kong paediatric immunology services. The Hong Kong PID Registry (Queen Mary Hospital / HKU) has documented cases.
In Hong Kong, newborn screening for SCID using TREC is being progressively implemented; however, WAS is not reliably detected by TREC-based newborn screening (because T-cell lymphopenia is variable and may not be severe enough at birth). Genetic testing and clinical suspicion remain paramount.
Consanguinity is uncommon in Hong Kong, but de novo mutations account for ~25–30% of WAS cases globally.

Family history of WAS or X-linked thrombocytopenia (XLT) in maternal male relatives
Known carrier mother (identified through genetic testing or family history of affected males)
Male sex (X-linked inheritance)

3. Anatomy and Function: The WASp Protein and Actin Cytoskeleton

Located on the short arm of the X chromosome (Xp11.22–p11.23).
Contains 12 exons encoding the 502-amino-acid WASp protein.
Expression is restricted to haematopoietic cells: T cells, B cells, NK cells, macrophages, dendritic cells, neutrophils, megakaryocytes, and platelets.

WASp is an intracellular scaffold/signalling protein that acts as a molecular bridge between surface receptor signalling and the actin cytoskeleton. Think of it as the "project manager" that tells actin filaments when, where, and how to reorganise.

Key structural domains (from N-terminus to C-terminus):

Domain	Function
WH1 (WASp Homology 1) / EVH1	Binds WIP (WASp-interacting protein) → stabilises WASp and prevents degradation
Basic region	Binds PIP2 (phosphatidylinositol 4,5-bisphosphate) in the membrane → membrane localisation
GBD (GTPase-binding domain) / CRIB	Binds active Cdc42 (a Rho-family GTPase) → "unlocks" WASp from its autoinhibited conformation
Proline-rich region	Binds SH3-domain-containing adaptor proteins (e.g., Nck, Grb2) → integrates signalling
VCA (Verprolin-homology, Central, Acidic)	Binds and activates the Arp2/3 complex → nucleates branched actin polymerisation

The actin cytoskeleton is not just structural scaffolding — it is the "engine" for:

Immune synapse formation (T cell–APC interaction): T cells must reorganise their cytoskeleton to form the ring-like structure where TCR clusters meet MHC-peptide on APCs. Without WASp → poor T-cell activation.
Cell migration and chemotaxis: Immune cells must crawl toward sites of infection. This requires polarised actin polymerisation at the leading edge. Without WASp → sluggish migration.
Phagocytosis: Macrophages and neutrophils extend pseudopods around pathogens — an actin-dependent process. Without WASp → impaired engulfment.
Platelet formation and function: Megakaryocytes use cytoskeletal remodelling to produce proplatelets (long extensions from which platelets bud off). Without WASp → abnormal megakaryocyte cytoskeleton → production of small, defective platelets that are rapidly cleared → microthrombocytopenia.
NK cell cytotoxicity: NK cells must polarise their cytotoxic granules toward the target cell — actin-dependent. Without WASp → reduced NK killing.
B-cell signalling and antibody production: BCR signalling involves cytoskeletal reorganisation. Without WASp → poor B-cell responses, especially to polysaccharide antigens.

Key Concept – Why Micro-thrombocytopenia?

The platelets in WAS are characteristically small (low MPV, mean platelet volume ~3.5–5.0 fL vs normal 7–11 fL). This is virtually pathognomonic and distinguishes WAS from most other causes of thrombocytopenia where platelets are normal or large. The mechanism:

Abnormal proplatelet formation: WASp-deficient megakaryocytes have disorganised cytoskeletons → produce structurally defective, small platelets.
Accelerated peripheral destruction: These abnormal platelets are rapidly cleared by the spleen (and possibly by anti-platelet autoantibodies that develop over time).
Splenic sequestration: The spleen acts as a filter, and small defective platelets are preferentially trapped.

This is why splenectomy can partially correct thrombocytopenia — but at the cost of further immunocompromise.

4. Aetiology

WAS is caused by mutations in the WAS gene on Xp11.22-p11.23, inherited in an X-linked recessive pattern. ^[1]^[2]

Over 400 unique mutations have been reported, including:
- Missense mutations (most common in milder phenotypes / XLT)
- Nonsense mutations (often severe WAS phenotype)
- Splice-site mutations
- Small insertions/deletions (indels)
- Large deletions (rare but severe)
- De novo mutations: approximately 25–30% of cases have no family history

This is a spectrum disease. The severity depends on how much residual WASp is produced:

Mutation Type	WASp Expression	Clinical Phenotype	Severity Score
Missense (esp. in WH1 domain)	Reduced but present	X-linked thrombocytopenia (XLT) — isolated microthrombocytopenia ± mild eczema, minimal immunodeficiency	1–2
Missense (other domains)	Variably reduced	Intermediate WAS	2–3
Nonsense / frameshift / splice-site	Absent	Classic WAS — full tetrad with severe immunodeficiency	3–5
Gain-of-function (VCA domain)	Constitutively active	X-linked neutropenia (XLN) — congenital neutropenia	Variable

Clinical severity scoring system (Zhu et al., modified from Ochs): Score 1–5 based on presence of thrombocytopenia only (score 1) to full-blown WAS with autoimmunity/malignancy (score 5).

Mutations in the WAS gene have been documented in Hong Kong Chinese families.
Hotspot mutations identified in some Chinese cohorts include mutations in exons 1–4 (affecting the WH1 domain) and exon 10 (affecting the VCA domain).
Genetic diagnosis is performed at the Department of Paediatrics & Adolescent Medicine, HKU, using targeted gene sequencing or whole-exome sequencing (WES).

5. Pathophysiology — Connecting the Gene Defect to Clinical Features

Let me walk you through the pathophysiology systematically, linking each molecular defect to the clinical manifestation:

Defective megakaryopoiesis: WASp-deficient megakaryocytes have disorganised actin cytoskeletons → abnormal proplatelet formation → small platelets (MPV typically < 5 fL).
Accelerated destruction: Abnormal platelets are recognised and destroyed by splenic macrophages. Over time, autoantibodies against platelet glycoproteins (GP IIb/IIIa, GP Ib/IX) develop, further accelerating destruction (similar to ITP but on a background of intrinsic platelet defect).
Net result: Platelet counts typically 10,000–50,000/μL with characteristically small platelet size.

T-cell defects:

Impaired immune synapse formation → defective T-cell activation in response to antigen presentation
Impaired T-cell migration → reduced ability to reach infection sites
Progressive T-cell lymphopenia over time (accelerated apoptosis of WASp-deficient T cells)
T-cells are affected in WAS ^[2]

B-cell defects:

Impaired BCR signalling → poor antibody responses, especially to T-independent antigens (polysaccharide antigens of encapsulated bacteria)
Low IgM is characteristic ^[2]; IgG may be normal or low; IgA and IgE are often elevated
Abnormal marginal zone B-cell function → vulnerability to encapsulated organisms

NK cell defects:

Impaired actin-dependent polarisation of cytotoxic granules → reduced NK cell-mediated killing → vulnerability to viral infections and malignancy

Innate immune defects:

Impaired neutrophil/macrophage chemotaxis (actin-dependent crawling)
Impaired phagocytosis
Impaired dendritic cell migration to lymph nodes → poor antigen presentation

The eczema in WAS is clinically indistinguishable from atopic dermatitis and often severe. The pathogenesis is multifactorial:

Immune dysregulation with Th2 skewing: WASp deficiency leads to impaired regulatory T-cell (Treg) function → loss of immune tolerance → exaggerated Th2 responses → elevated IgE → atopic-type inflammation.
Skin barrier dysfunction: While WASp is not expressed in keratinocytes, the immune-mediated inflammation damages the skin barrier secondarily.
Susceptibility to skin infections: Impaired local immune responses → secondary infection with S. aureus, herpes simplex → eczema herpeticum, further exacerbating skin inflammation.

Autoimmunity is a major feature of WAS, occurring in 40–70% of patients with classic WAS:

Mechanism: Defective Treg function (WASp is critical for Treg suppressive function) + impaired peripheral tolerance + defective clearance of apoptotic cells → autoantibody production
Common autoimmune manifestations:
- Autoimmune haemolytic anaemia (AIHA) — most common
- Autoimmune neutropenia
- IgA nephropathy / vasculitis (including HSP-like vasculitis)
- Inflammatory bowel disease-like colitis
- Autoimmune arthritis
- Cerebral vasculitis

Risk: approximately 13–22% lifetime risk of malignancy, increasing with age
Types: predominantly lymphoid malignancies — EBV-driven lymphoproliferative disease, non-Hodgkin lymphoma (especially B-cell lymphoma), and leukaemia
Mechanism: Impaired immune surveillance (defective NK and T-cell cytotoxicity) + chronic immune stimulation + inability to control EBV (a known lymphomagenic virus)

6. Classification

WAS is classified under:

Category 2: Combined immunodeficiencies with associated or syndromic features (15.2% of all PIDs) ^[1]^[2]

This is because WAS involves both T-cell and B-cell dysfunction plus syndromic features (thrombocytopenia, eczema). It is not a pure combined immunodeficiency (which would be Category 1, e.g., SCID).

All three conditions below are caused by mutations in the same WAS gene — they differ in severity:

Entity	WASp Expression	Key Features	Severity
X-linked thrombocytopenia (XLT)	Reduced	Microthrombocytopenia ± mild eczema; minimal immunodeficiency	Mild
Classic Wiskott-Aldrich syndrome	Absent	Full tetrad: microthrombocytopenia + eczema + immunodeficiency + bloody diarrhoea; autoimmunity and malignancy risk	Severe
X-linked neutropenia (XLN)	Constitutively active (gain-of-function)	Congenital neutropenia ± myelodysplasia	Variable

Score	Features
1	Intermittent thrombocytopenia, small platelets only
2	Persistent thrombocytopenia + mild eczema, minor infections
3	Eczema responsive to therapy + recurrent infections not life-threatening
4	Eczema difficult to control + severe/life-threatening infections
5	Autoimmune disease and/or malignancy

7. Clinical Features

Most present in infancy (first few months of life).
Common initial presentations:
- Petechiae or purpura at birth or early infancy
- Bloody diarrhoea (haematochezia) in the neonatal/early infantile period
- Eczema appearing in the first months of life
- Prolonged bleeding after circumcision (relevant in some populations)
- Recurrent infections — otitis media, pneumonia, skin infections

Symptom	Pathophysiological Basis
Eczema — pruritic, erythematous, weeping/crusted rash, often severe and refractory to standard treatment	Th2-skewed immune dysregulation → excessive IgE production → atopic inflammation; impaired Treg function → inability to downregulate skin inflammation; secondary infection with S. aureus worsens the cycle
Bleeding symptoms: petechiae, purpura, ecchymoses, epistaxis, oral mucosal bleeding, haematochezia (bloody diarrhoea), haematuria, prolonged bleeding from cuts/circumcision	Microthrombocytopenia — both reduced platelet count AND qualitative platelet dysfunction (defective actin-dependent shape change and granule release) → inadequate primary haemostasis
Recurrent infections: otitis media, sinusitis, pneumonia (bacterial); skin infections (bacterial/viral); oral candidiasis; opportunistic infections (PJP, CMV, HSV, VZV); severe/disseminated viral infections	Combined T-cell and B-cell dysfunction → vulnerability to bacteria (especially encapsulated organisms due to poor anti-polysaccharide antibody responses), viruses, fungi; impaired NK cells → poor viral clearance; impaired phagocyte chemotaxis
Bloody diarrhoea / chronic diarrhoea	(a) Thrombocytopenia → GI mucosal bleeding; (b) Immune dysregulation → autoimmune enteropathy / IBD-like colitis; (c) GI infections
Failure to thrive / poor weight gain	Chronic infection + chronic diarrhoea + chronic inflammation + poor nutrient absorption
Fatigue / pallor	Chronic blood loss (GI, mucosal) → iron deficiency anaemia; autoimmune haemolytic anaemia (AIHA); chronic disease
Symptoms of autoimmune disease (varies): joint pain/swelling, rash, dark urine, jaundice	Autoimmune arthritis, vasculitis, AIHA, glomerulonephritis — all due to impaired Treg function and loss of self-tolerance
Lymphadenopathy / hepatosplenomegaly — progressive	Chronic immune stimulation, lymphoproliferation, splenomegaly from platelet trapping and extramedullary haematopoiesis; may herald lymphoma

Sign	Pathophysiological Basis
Petechiae and purpura — especially over trunk, extremities, and mucous membranes	Microthrombocytopenia → capillary bleeding without adequate platelet plug formation
Eczematous dermatitis — resembles severe atopic dermatitis; may be generalised; often superinfected (impetiginised / eczema herpeticum)	See above — Th2 skewing, barrier dysfunction, secondary infection
Hepatosplenomegaly	Splenic sequestration of abnormal platelets; chronic immune activation; extramedullary haematopoiesis; if massive, consider lymphoproliferative disease
Lymphadenopathy	Chronic antigenic stimulation; immune dysregulation; if rapidly enlarging, consider lymphoma
Signs of secondary infection: fever, cellulitis, oral thrush, herpetic lesions, lung crackles	Immunodeficiency → susceptibility to bacterial, viral, and fungal pathogens
Pallor	Anaemia from chronic blood loss, AIHA, or bone marrow suppression
Jaundice (if AIHA)	Haemolysis → unconjugated hyperbilirubinaemia
Signs of intracranial haemorrhage (ICH): bulging fontanelle, altered consciousness, seizures, focal neurological deficit	Severe thrombocytopenia → risk of spontaneous ICH — a leading cause of death in WAS. Infants with platelet counts < 10,000/μL are at highest risk
Joint swelling / vasculitic rash (if autoimmune complication)	Autoimmune arthritis / vasculitis from loss of immune tolerance
Growth faltering / wasting — plot on growth chart	Chronic infection, diarrhoea, inflammation → failure to thrive

Clinical Pearl – Distinguishing WAS Eczema from Typical Atopic Dermatitis

The eczema of WAS can be clinically indistinguishable from atopic dermatitis (AD). However, key clues to WAS include:

Associated thrombocytopenia (petechiae within or around eczema patches — "bleeding into the eczema")
Recurrent infections disproportionate to the severity of eczema
Male sex with X-linked family history
Onset in early infancy with bloody diarrhoea
Refractory to standard AD treatment

Always check a CBC with platelet count and MPV in any male infant with severe eczema — this single test can raise suspicion for WAS.

Important – ICH is a Leading Cause of Death

Intracranial haemorrhage (ICH) is a feared complication and historically a leading cause of mortality in WAS (accounts for ~20% of deaths). It can occur spontaneously when platelets are critically low (< 10,000–20,000/μL). Always assess for signs of raised ICP in a child with WAS and acute neurological changes.

Parameter	Typical Finding in Classic WAS	Explanation
Platelet count	Low (typically 10,000–50,000/μL)	Defective production + accelerated destruction
Mean platelet volume (MPV)	Low (< 5 fL; normal 7–11 fL) — pathognomonic	Small platelets due to defective cytoskeleton-dependent proplatelet formation
IgM	Low ^[2]	Poor T-independent B-cell responses; accelerated IgM catabolism
IgG	Normal or slightly low	Variable; may decline over time
IgA	Normal or elevated	Mucosal immune compensation
IgE	Often elevated	Th2 skewing → class switching to IgE
Isohemagglutinins	Absent or low	These are IgM anti-A or anti-B antibodies → reflects poor IgM production
Anti-polysaccharide antibodies	Poor/absent	B-cell dysfunction, especially against T-independent antigens
T-cell count	Progressive lymphopenia (may be normal early)	Accelerated T-cell apoptosis; impaired T-cell proliferation
T-cell function (proliferation assays)	Reduced	Impaired immune synapse formation
NK cell function	Reduced	Defective actin-dependent granule polarisation

Median survival without HSCT: historically <15 years (improved with supportive care to ~20 years in modern era without definitive treatment)
Causes of death: infection (~50%), bleeding including ICH (~25%), malignancy (~25%)
Disease worsens progressively — the immunodeficiency becomes more severe over time as T-cell numbers decline
Autoimmune complications and malignancy risk increase with age

8. Family-Centred Care and Communication Considerations (Paediatric)

Explain the X-linked inheritance pattern — important for genetic counselling:
- Mother is a carrier (50% chance each son affected; 50% chance each daughter is a carrier)
- Offer carrier testing to maternal female relatives
- Discuss prenatal/preimplantation genetic testing for future pregnancies
Multidisciplinary team approach: paediatric immunologist, haematologist, dermatologist, geneticist, social worker, clinical psychologist
Psychosocial support: chronic illness in infancy is distressing for families; address parental guilt (especially mothers who are carriers)

Neonates/infants: Parents are the primary decision-makers; explain diagnosis, need for urgent treatment, and prognosis clearly
Older children/adolescents: Involve the child in discussions as developmentally appropriate (assent); explain the condition in age-appropriate language
Consent: Parents consent for investigations and treatments; assent from the child when old enough (usually > 7 years in Hong Kong)

Avoidance of live vaccines (BCG, MMR, OPV, varicella, rotavirus) until immune status clarified
Prompt medical attention for fevers
Prophylactic antibiotics and IVIG adherence

This table is high-yield for exams — you must be able to compare WAS with DiGeorge, Hyper-IgE, Ataxia-Telangiectasia, and X-linked Lymphoproliferative disease.

Feature	WAS	DiGeorge	Hyper-IgE (HIES)	Ataxia-Telangiectasia	X-linked Lymphoproliferative (Duncan)
Inheritance	X-linked recessive	AD (22q11.2 del)	AD (STAT3 LOF)	AR (ATM gene)	X-linked recessive (SH2D1A)
Gene	WAS	TBX1/22q11.2	STAT3	ATM	SH2D1A
Immune defect	Combined (T+B+NK)	T-cell (thymic hypoplasia)	T-cell (Th17)	Combined (T+B)	T/NK cell dysfunction
Key triad/features	Eczema + microthrombocytopenia + immunodeficiency ^[1]	Cardiac + thymic hypoplasia + hypoparathyroid ^[1]	Pneumatocele + cold Staph abscesses + mucocutaneous candidiasis + retained primary teeth + minimal trauma fractures ^[1]^[2]	Cerebellar ataxia + telangiectasia + lymphoma risk ^[1]	Abnormal response to EBV → fulminant infection or lymphoma ^[1]
IgE	↑	Normal	Markedly ↑ ^[2]	Normal	Normal
Platelets	Low + small	Normal	Normal	Normal	Normal

High Yield Summary

Wiskott-Aldrich Syndrome (WAS) — Key Points for Exams:

Definition: X-linked recessive PID caused by loss-of-function mutations in the WAS gene → absent/dysfunctional WASp → defective actin cytoskeleton in all haematopoietic cells.
Classification: IUIS Category 2 — Combined immunodeficiency with associated/syndromic features.
Classic tetrad: Eczema + Microthrombocytopenia (low count AND small size) + Immunodeficiency + Bloody diarrhoea.
Pathognomonic feature: Microthrombocytopenia — platelets are BOTH low in number AND small (low MPV < 5 fL). This is virtually unique to WAS.
Immunological profile: Low IgM, often elevated IgE and IgA, poor anti-polysaccharide antibody responses, progressive T-cell lymphopenia, impaired NK function.
Genotype-phenotype spectrum: Missense → XLT (mild); Null mutations → classic WAS (severe); Gain-of-function → XLN (neutropenia).
Complications: Autoimmunity (40–70%), malignancy (13–22%, especially lymphoma), ICH (leading cause of death).
Definitive treatment: Haematopoietic stem cell transplantation (HSCT) — curative. Gene therapy is emerging.
Key differential: Any male infant with severe eczema → check CBC + MPV. Small platelets distinguish WAS from ITP (where platelets are large).
Inheritance: X-linked recessive → affects males; carrier testing and genetic counselling for maternal relatives essential.

Active Recall - Wiskott-Aldrich Syndrome

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p411 — WAS listed under CID with associated/syndromic features, triad, DiGeorge, Hyper-IgE, XLP, Ataxia-Telangiectasia) ^[2] Senior notes: Jerry's immunodeficiencies.pdf (p2 — WAS tetrad: eczema, microthrombocytopenia, immunodeficiency, bloody diarrhoea; low IgM; T-cells affected; IUIS classification) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p638 — PID categories, SCID features, features suggestive of PID) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (p10 — approach to PID diagnosis, phenotypic investigations, genetic testing) ^[5] Senior notes: Maksim Medicine Notes.pdf (p161 — platelet disorders differential: WAS listed under congenital quantitative platelet disorders) ^[6] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf ^[7] Lecture slides: GC 096. Why do I always get sick.pdf ^[8] Senior notes: Ryan Ho Haemtology.pdf (p117 — ITP pathogenesis and platelet destruction mechanisms) ^[9] Senior notes: Block A - Fundamentals of Allergology.pdf (p3 — Type 1 vs Type 4 hypersensitivity, IgE and atopy) ^[10] Senior notes: Ryan Ho Rheumatology.pdf (p113 — Atopic dermatitis pathogenesis, filaggrin, barrier dysfunction)

When you encounter a male infant or young child with the WAS-like constellation — eczema + thrombocytopenia + bleeding + recurrent infections — you must systematically work through the differential diagnosis. The key is to realise that WAS sits at the intersection of three clinical domains, and the DDx differs depending on which presenting feature brings the patient to medical attention:

Thrombocytopenia / bleeding — the most common initial presentation in neonates/infants
Eczema / atopic dermatitis — may be the first thing noticed by parents or the GP
Recurrent infections / immunodeficiency — may become apparent later in infancy

The pathognomonic clue that narrows the differential dramatically is microthrombocytopenia — platelets that are both low in count AND small in size (low MPV). This finding is virtually unique to WAS/XLT among all causes of thrombocytopenia.

Let me walk you through each domain systematically.

A. Differential Diagnosis by Presenting Feature

A1. Male Infant with Thrombocytopenia ± Bleeding

This is the most common way WAS first declares itself — petechiae, purpura, or bloody diarrhoea in a male infant.

Condition	Platelet Size	Key Distinguishing Features	Why It Can Mimic WAS
Wiskott-Aldrich syndrome / X-linked thrombocytopenia (XLT)	Small (↓MPV)	Eczema, immunodeficiency, bloody diarrhoea; X-linked; WAS gene mutation ^[1]^[2]	— (this IS WAS)
Bernard-Soulier syndrome (BSS)	Large (↑MPV — "giant platelets")	Defective GPIb/IX/V complex → impaired platelet adhesion to vWF; AR inheritance; typically no eczema or immunodeficiency ^[3]^[5]	Thrombocytopenia + mucocutaneous bleeding in a young child. Key distinguisher: platelets are LARGE, not small. No eczema. No immunodeficiency.
May-Hegglin anomaly	Large	AD inheritance; Döhle-body-like inclusions in neutrophils on PBS; MYH9-related disorder ^[5]	Congenital thrombocytopenia with large platelets. No eczema, no immunodeficiency.
Congenital amegakaryocytic thrombocytopenia (CAMT)	Normal-to-large	MPL gene mutation → absent megakaryocytes; severe thrombocytopenia at birth; progresses to aplastic anaemia	Severe neonatal thrombocytopenia. No eczema. No immunodeficiency (initially). Bone marrow shows absent megakaryocytes.
Thrombocytopenia-absent radius (TAR) syndrome	Normal	Bilateral absent radii with thumbs present; thrombocytopenia improves with age	Neonatal thrombocytopenia but obvious skeletal anomaly. No eczema.
Fanconi anaemia	Normal	Progressive pancytopenia (not just thrombocytopenia); dysmorphic features (short stature, café-au-lait spots, thumb/radial anomalies); chromosomal breakage test positive ^[4]^[9]	Can present with thrombocytopenia in early childhood but usually pancytopenia; dysmorphic features differ from WAS.
MYH9-related disorders (Fechtner, Sebastian, Epstein syndromes)	Large	Sensorineural hearing loss, nephritis, cataracts depending on subtype; neutrophil inclusions	Congenital thrombocytopenia but large platelets and distinctive extra-haematological features.

The MPV Is Your Best Friend

In any infant or child presenting with thrombocytopenia, always check the mean platelet volume (MPV). This single number dramatically narrows the differential:

Small platelets (MPV < 5 fL): virtually pathognomonic for WAS/XLT
Large platelets (MPV > 11 fL): think Bernard-Soulier, MYH9-related disorders, May-Hegglin anomaly, or ITP (where large platelets reflect increased bone marrow production in response to peripheral destruction)
Normal platelets: ITP, bone marrow failure syndromes, consumption coagulopathies

This is a simple test that can be done on any standard CBC — don't overlook it.

Condition	Mechanism	Key Distinguishing Features	Why It Can Mimic WAS
Immune thrombocytopenia (ITP)	Anti-platelet autoantibodies (anti-GPIIb/IIIa, anti-GPIb/IX) → premature platelet destruction in spleen ^[8]	Most common cause of isolated thrombocytopenia in children; typically self-limiting in children (80% resolve within 6 months); often follows viral infection; NO eczema, NO immunodeficiency; platelets are LARGE (high MPV) because marrow compensates by producing bigger platelets	Mucocutaneous bleeding in a young child. Key distinguisher: platelets are LARGE. No eczema. No recurrent infections. Previously well child.
Neonatal alloimmune thrombocytopenia (NAIT)	Maternal antibodies against paternally derived platelet antigens (usually HPA-1a) cross placenta → destroy fetal/neonatal platelets	Presents at birth; severe thrombocytopenia; resolves in weeks; mother's platelet count is normal	Neonatal thrombocytopenia. Self-limiting. No eczema. No immunodeficiency.
Infection-associated thrombocytopenia	Viral (CMV, EBV, HIV, dengue, parvovirus B19); bacterial sepsis; DIC	Acute illness with fever; thrombocytopenia in context of systemic infection; resolves with treatment of underlying infection	Thrombocytopenia + fever/infection could superficially mimic WAS, but this is acute and not recurrent. No eczema.
Haemolytic uraemic syndrome (HUS)	MAHA + thrombocytopenia + AKI; usually post-diarrhoeal (E. coli O157:H7) in children ^[5]^[6]	Triad of MAHA (schistocytes on PBS) + thrombocytopenia + renal failure; bloody diarrhoea precedes	Bloody diarrhoea + thrombocytopenia in a child → could be confused with WAS. Key distinguisher: schistocytes on PBS, renal failure, acute onset. No eczema. No immunodeficiency.
DIC	Consumption of platelets and clotting factors in setting of severe illness (sepsis, malignancy, trauma) ^[5]	Prolonged PT and APTT, low fibrinogen, elevated D-dimer, schistocytes; critically ill child	Thrombocytopenia in a sick child. Obvious trigger. Multi-system derangement.
Bone marrow infiltration (leukaemia / lymphoma)	Malignant cells replace normal haematopoiesis → pancytopenia	Pallor, fever, bone pain, hepatosplenomegaly, lymphadenopathy; blasts on PBS or bone marrow; pancytopenia rather than isolated thrombocytopenia ^[10]	Thrombocytopenia + bleeding + infections. Key distinguisher: pancytopenia (not isolated thrombocytopenia), blasts, organomegaly, bone pain.
Acquired aplastic anaemia	Immune-mediated destruction of haematopoietic stem cells → pancytopenia ^[4]^[9]	Pancytopenia; NO lymphadenopathy; NO hepatosplenomegaly; hypocellular bone marrow replaced by fat ^[4]^[9]	Thrombocytopenia + infections (neutropenia). Key distinguisher: pancytopenia, reticulocytopenia, hypocellular marrow. No eczema.
Hypersplenism	Splenic pooling of platelets	Splenomegaly; mild thrombocytopenia; underlying cause (portal hypertension, storage diseases)	Thrombocytopenia + splenomegaly. No eczema. No immunodeficiency (unless underlying cause).
Drug-induced thrombocytopenia	Drug-dependent antibodies (e.g., ibuprofen, ampicillin, valproate); or direct marrow suppression (chemotherapy) ^[5]^[6]	Clear temporal relationship with drug exposure	Rare in neonates. History of drug exposure.

The eczema in WAS is clinically indistinguishable from atopic dermatitis (AD). The differential here is really about recognising the eczema-plus-something-else pattern.

Genetic/metabolic/immunodeficiency syndromes featuring eczema with or without raised IgE: Ataxia telangiectasia, Wiskott-Aldrich syndrome ^[11]

Differential diagnosis of eczema includes: seborrhoeic dermatitis, contact dermatitis, psoriasis, scabies, and genetic or metabolic disorders featuring atopic eczema with or without raised IgE level — e.g. Ataxia telangiectasia, Wiskott-Aldrich syndrome ^[11]

Condition	Eczema Characteristics	Key Distinguishing Features
Atopic dermatitis (idiopathic)	Age-typical distribution (face/extensors in infants → flexures in older children); pruritic; responds to emollients + topical steroids	Most common DDx. Normal platelets. Normal immune function. Family history of atopy (not X-linked PID). No recurrent infections disproportionate to eczema severity.
Wiskott-Aldrich syndrome	Identical to AD clinically; often severe and refractory	Microthrombocytopenia + immunodeficiency + male sex + X-linked FHx ^[1]^[2]
Hyper-IgE syndrome (HIES)	Eczematous dermatitis; often with cold staphylococcal abscesses	Markedly elevated IgE; pneumatoceles; mucocutaneous candidiasis; retained primary teeth; minimal trauma fractures; STAT3 mutation (AD) ^[1]^[2]. No thrombocytopenia.
Severe combined immunodeficiency (SCID)	Erythroderma (diffuse skin inflammation from maternal T-cell engraftment / Omenn syndrome) or eczema-like rash	Severe lymphopenia (ALC < 2500/μL in infants); absent thymic shadow; failure to thrive; life-threatening infections from early infancy ^[2]. Much more severe immunodeficiency than WAS.
DiGeorge syndrome	Eczema can occur but not as a primary feature	Conotruncal cardiac anomalies + hypoplastic thymus (T-cell deficiency) + hypoparathyroidism (hypocalcaemia); 22q11.2 deletion ^[1]. Dysmorphic facies. No thrombocytopenia.
Ataxia telangiectasia	Eczema can occur	Cerebellar ataxia (progressive); oculocutaneous telangiectasia (usually age > 3 years); developmental delay; elevated AFP; lymphoma risk; ATM gene mutation (AR) ^[1]. No thrombocytopenia.
IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked)	Severe eczematous dermatitis in male infants	FOXP3 mutation; neonatal-onset type 1 diabetes; severe watery diarrhoea (autoimmune enteropathy); thyroiditis. No thrombocytopenia.
Netherton syndrome	Ichthyosiform erythroderma; "bamboo hair" (trichorrhexis invaginata)	SPINK5 mutation (AR); hair shaft abnormality; elevated IgE; no thrombocytopenia; no immunodeficiency.
Seborrhoeic dermatitis	Greasy, salmon-coloured, scaly patches on scalp, face, nappy area; little pruritus ^[7]	Most common differential of eczema in infants ^[7]. Self-limiting. No thrombocytopenia. No immunodeficiency.
Scabies	Diffuse pruritic eruption; vesicopustules on palms and soles ^[7]	Positive skin scraping for mites. Household contacts often affected. No thrombocytopenia.

High Yield – When to Suspect WAS in a Child with 'Just Eczema'

Do NOT dismiss severe eczema in a male infant as "just atopic dermatitis" without checking a CBC. If the CBC shows thrombocytopenia with small platelets (low MPV), you must suspect WAS. The eczema of WAS is often refractory to standard treatment and may have petechiae within or around the lesions — "bleeding into the eczema." Thrombocytopenia may occur in Wiskott-Aldrich syndrome — this was specifically flagged in the dermatology and paediatrics notes ^[7].

When the presenting feature is recurrent infections, the DDx pivots to the primary immunodeficiency spectrum. The IUIS classification helps organise this systematically.

Table 2 — combined immunodeficiency with associated or syndromic features (e.g. Wiskott-Aldrich syndrome) ^[12]

PID Category	Example	Immune Defect	Key Distinguishing Features from WAS
Category 1: Combined immunodeficiency (CID)	SCID	T + B cells; low TREC; low ALC < 2500/μL; low/zero T-cell count ^[2]	More severe than WAS; presents earlier (often < 3 months); absent thymic shadow; failure to thrive. No thrombocytopenia. Definitive Rx is HSCT ^[2].
Category 2: CID with syndromic features	WAS	T cells (progressive); also B, NK	Eczema + microthrombocytopenia + immunodeficiency + bloody diarrhoea ^[1]^[2]
	Hyper-IgE syndrome	T cells (Th17); high IgE; high AEC; CXR showing massive pneumatoceles ^[2]	Cold Staph abscesses; retained primary teeth; minimal trauma fractures. No thrombocytopenia. STAT3 LOF (AD) ^[2].
	DiGeorge syndrome	T cells (thymic hypoplasia)	Conotruncal cardiac anomalies + thymic hypoplasia + hypoparathyroidism (hypoCa); 22q11.2 deletion ^[1]. No thrombocytopenia.
	Ataxia telangiectasia	Combined T + B	Cerebellar ataxia; telangiectasia; elevated AFP; lymphoma risk; developmental delay ^[1]. No thrombocytopenia.
	X-linked lymphoproliferative disease (Duncan)	T/NK cells	Abnormal response to EBV → fulminant infection or lymphoma ^[1]; SH2D1A mutation. No thrombocytopenia.
Category 3: Predominantly antibody deficiency	X-linked agammaglobulinaemia (XLA / Bruton)	B cells; low KREC; absent B cells; all Ig classes severely reduced ^[2]	Bacterial infections after maternal antibody wanes (~6 months); no eczema; no thrombocytopenia; absent tonsils/lymphoid tissue. BTK mutation (X-linked) ^[2].
	CVID	B cells (variable)	Older age of onset (usually > 2 years, often adolescent/adult); recurrent sinopulmonary infections; autoimmune cytopenias possible but no microthrombocytopenia; no eczema ^[12].
Category 5: Phagocyte defects	Chronic granulomatous disease (CGD)	Phagocytes (NADPH oxidase deficiency); fail to produce superoxide → inability to destroy catalase-positive organisms ^[1]	Recurrent pyogenic infections with granuloma formation; common sites: lung, skin, LNs, liver; lymphadenitis, hepatosplenomegaly, skin/perianal abscess, TB/BCG dissemination; no eczema; no thrombocytopenia ^[1].
	Leukocyte adhesion deficiency (LAD)	Neutrophils (CD18 deficiency); ↑neutrophil count (trapped in vasculature) ^[1]	Poor wound healing with absent pus formation; omphalitis with delayed umbilical cord separation ^[1]; no eczema; no thrombocytopenia.
Category 8: Complement deficiency	Early/late component deficiency	Complement	Recurrent infections with encapsulated bacteria (esp. Neisseria); SLE-like illness (early components). No eczema; no thrombocytopenia ^[1].

Very few conditions produce both eczema AND thrombocytopenia in a paediatric patient. This narrows the DDx considerably:

Condition	Eczema	Thrombocytopenia	Platelet Size	Immunodeficiency	Other Key Features
WAS	Yes (severe)	Yes	Small	Yes (combined)	X-linked; bloody diarrhoea; autoimmunity; malignancy risk
SCID (Omenn phenotype)	Erythroderma (not classic eczema)	Possible (but not primary)	Normal	Severe	Lymphopenia; absent thymic shadow; failure to thrive
Hyper-IgE syndrome	Yes	No (usually)	N/A	Yes (Th17)	Massively elevated IgE; cold abscesses; pneumatoceles
IPEX syndrome	Yes (severe)	Possible (autoimmune)	Normal/Large	Yes (Treg deficiency)	Neonatal diabetes; autoimmune enteropathy; FOXP3 mutation
ITP + coincidental atopic dermatitis	Yes (atopic)	Yes	Large	No	Two separate common conditions co-occurring; no immunodeficiency
Leukaemia with skin infiltration	Possible (but not typical eczema)	Yes (marrow failure)	Normal	Functional (marrow replacement)	Pancytopenia; blasts; organomegaly; bone pain

High Yield – The Exam Shortcut

If you see a male infant with eczema + thrombocytopenia + small platelets on CBC → the answer is WAS until proven otherwise.

WAS must be considered in young males with thrombocytopenia and small platelets particularly if there is a history of eczema and recurrent infection ^[3]^[6].

The MPV (mean platelet volume) is the single most discriminating test. Small platelets (low MPV) in a thrombocytopenic male infant = WAS.

When approaching the differential diagnosis, think in layers:

Layer 1 — Is the thrombocytopenia real?

Rule out pseudothrombocytopenia (EDTA-induced platelet clumping on CBC → check PBS) ^[5]
Rule out specimen error

Layer 2 — Is it isolated thrombocytopenia or pancytopenia?

Isolated thrombocytopenia → ITP, WAS, BSS, NAIT, consumption (HUS/DIC)
Pancytopenia → aplastic anaemia, leukaemia, bone marrow failure syndromes

Layer 3 — What is the platelet size?

Small (↓MPV): WAS/XLT — virtually nothing else does this
Large (↑MPV): ITP, BSS, MYH9-related, May-Hegglin
Normal: NAIT, consumption, marrow failure

Layer 4 — Are there associated features?

- Eczema → WAS, HIES, SCID/Omenn, IPEX
- Recurrent infections → WAS, SCID, CGD, XLA, HIES
- Cardiac anomalies + hypocalcaemia → DiGeorge
- Skeletal anomalies → TAR, Fanconi anaemia
- Renal failure + MAHA → HUS
- Blasts + bone pain → leukaemia

Layer 5 — Family history and inheritance pattern

X-linked (males only): WAS, XLA, SCID (IL2RG), CGD (most), XLP
Autosomal recessive: BSS, SCID (other), Fanconi, ataxia-telangiectasia
Autosomal dominant: HIES (STAT3), MYH9-related disorders

High Yield Summary – Differential Diagnosis of WAS

The WAS tetrad (eczema + microthrombocytopenia + immunodeficiency + bloody diarrhoea) is fairly unique; no other single condition perfectly replicates all four.
The MPV is the critical discriminating test: Small platelets (MPV < 5 fL) in a thrombocytopenic male infant = WAS until proven otherwise.
Most common DDx pitfalls in exams:
- Confusing WAS with ITP → ITP has LARGE platelets, no eczema, no immunodeficiency, previously well child
- Confusing WAS with atopic dermatitis → always check CBC in male infants with severe refractory eczema
- Confusing WAS with Bernard-Soulier → BSS has LARGE/giant platelets, no eczema, no immunodeficiency
Other PIDs with eczema: HIES (very high IgE, cold abscesses, pneumatoceles), SCID/Omenn (erythroderma, severe lymphopenia), IPEX (neonatal diabetes, enteropathy), DiGeorge (cardiac, hypoCa)
WAS is classified under IUIS Table 2 — combined immunodeficiency with associated or syndromic features ^[12]

Active Recall - DDx of Wiskott-Aldrich Syndrome

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p411 — WAS triad, DiGeorge, HIES, XLP, Ataxia-telangiectasia, CGD, LAD under PIDs with associated/syndromic features) ^[2] Senior notes: Jerry's immunodeficiencies.pdf (p2 — WAS tetrad, low IgM, IUIS classification, SCID, HIES, XLA) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p607 — congenital and acquired platelet disorder DDx, WAS in young males with small platelets) ^[4] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p8 — aplastic anaemia features, congenital causes) ^[5] Senior notes: Maksim Medicine Notes.pdf (p161 — platelet disorders DDx table: congenital vs acquired, quantitative vs qualitative) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p699 — DDx of purpura including WAS, BSS, acquired platelet disorders) ^[7] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1787 — DDx of eczema including WAS, HIES, DiGeorge, SCID, seborrhoeic dermatitis, scabies) ^[8] Senior notes: Ryan Ho Haemtology.pdf (p117 — ITP pathogenesis, anti-platelet antibodies, platelet destruction) ^[9] Senior notes: Ryan Ho Haemtology.pdf (p32 — aplastic anaemia pathophysiology, clinical features, no organomegaly) ^[10] AOS material: AOS - Paeds.pdf (p1 — AOS Q10: pallor, fever, bruising, bone pain → ALL vs AA vs ITP vs JIA) ^[11] Lecture slides: Dermatology I Basics of Dermatology.pdf (p21 — DDx of eczema including Ataxia telangiectasia, Wiskott-Aldrich syndrome) ^[12] Lecture slides: Investigations of Imm Disorders 2025.pdf (p7 — IUIS Tables 1–9, WAS under Table 2: CID with associated or syndromic features)

1. Diagnostic Criteria

Unlike some conditions (e.g., CVID with formal ESID criteria ^[14]), WAS does not have a single universally agreed-upon set of "diagnostic criteria" in the way that, say, rheumatic fever has Jones criteria. Instead, diagnosis is established through a combination of clinical features, laboratory findings, protein expression, and genetic confirmation. Think of it as a stepwise process: clinical suspicion → screening labs → confirmatory protein testing → definitive genetic diagnosis.

The following clinical constellation should trigger suspicion:

Suspect WAS in any male infant/child with:

Thrombocytopenia with small platelets (low MPV) — this is the earliest and most consistent feature ^[2]^[13]

Eczema — particularly if severe, early-onset, and refractory ^[2]

Recurrent infections — bacterial, viral, or opportunistic ^[2]

Bloody diarrhoea — secondary to microthrombocytopenia ^[2]

Family history of affected males on the maternal side (X-linked recessive)

PLT low → Wiskott-Aldrich syndrome ^[13] — this was specifically listed on the GC 144 lecture slide as the key CBC finding pointing to WAS.

Low IgM → DOCK8, Wiskott-Aldrich syndrome, ataxia-telangiectasia ^[13] — the GC slide also flags low IgM as a finding directing you toward WAS.

The diagnosis of WAS can be organised into three tiers:

Tier	Level of Diagnosis	Requirements
Tier 1: Probable / Clinical WAS	Clinical + haematological	Male with (a) congenital/early-onset thrombocytopenia AND (b) small platelet volume (MPV < 5 fL or platelet size consistently below normal on PBS) AND (c) ≥ 1 of: eczema, recurrent infections, autoimmunity, family history
Tier 2: Confirmed by Protein	Protein expression	Tier 1 criteria PLUS absent or markedly reduced WASp expression by flow cytometry or Western blot in peripheral blood lymphocytes
Tier 3: Definitive / Genetic	Genetic confirmation	Identification of a pathogenic mutation in the WAS gene (Xp11.22–p11.23) by targeted sequencing, gene panel, or whole-exome/genome sequencing

High Yield – Genetic Testing Is the Gold Standard

Genetic testing has an important role in: Diagnosis (All cases), Family studies, Prognostication, Prenatal diagnosis, Defining new diseases ^[14].

For WAS specifically, genetic confirmation is essential because:

It distinguishes classic WAS (null mutations, absent WASp) from X-linked thrombocytopenia (XLT) (missense mutations, reduced WASp) — this has major prognostic and therapeutic implications.
It enables carrier testing of maternal female relatives.
It enables prenatal diagnosis in subsequent pregnancies.
It allows preimplantation genetic testing (PGT) for families pursuing IVF.

Once WAS is diagnosed, severity is scored to guide management:

Score	Features	Typical Genotype
1	Intermittent thrombocytopenia, small platelets only; no eczema, no immunodeficiency	XLT (missense, WASp reduced)
2	Persistent thrombocytopenia + mild/transient eczema ± minor infections	XLT
3	Eczema responsive to therapy + recurrent infections not life-threatening	Intermediate
4	Eczema difficult to control + severe/life-threatening infections	Classic WAS (null, WASp absent)
5	Autoimmune disease and/or malignancy	Classic WAS

Scores 3–5 generally warrant HSCT as definitive management. Scores 1–2 may be managed conservatively with surveillance.

The following algorithm walks you through the clinical reasoning from initial suspicion to definitive diagnosis. This mirrors how a paediatric immunologist in Hong Kong would approach the case.

3. Investigation Modalities — Detailed Guide

I will walk you through every investigation, explaining what it is, why we do it, what we find in WAS, and how to interpret it. I have organised this from bedside screening tests → specialised immunological workup → definitive genetic diagnosis → supportive/monitoring investigations.

3.1 First-Line Screening Investigations

Why we do it: This is the single most important initial screening test. It can be done at any hospital or clinic and often provides the first clue to WAS.

Complete blood count — PLT low → Wiskott-Aldrich syndrome ^[13]

Parameter	Expected Finding in WAS	Interpretation / Pathophysiological Basis
Platelet count	Low (typically 10,000–50,000/μL) ^[2]	Defective proplatelet formation from WASp-deficient megakaryocytes + accelerated peripheral destruction
Mean Platelet Volume (MPV)	Low (< 5 fL; normal 7–11 fL) — pathognomonic	Small platelets due to defective actin cytoskeleton in megakaryocytes → abnormal proplatelet budding. This is the single most discriminating finding.
Haemoglobin	May be low (anaemia)	Chronic blood loss (GI, mucosal) → iron deficiency; AIHA (if autoimmune complication present); chronic disease
White cell count	Usually normal initially; may show lymphopenia over time	Progressive T-cell lymphopenia from accelerated apoptosis
Absolute lymphocyte count (ALC)	May be low (especially in older children)	Normal paediatric ALC: < 1 year > 3000/μL; > 1 year > 1000/μL ^[13]. Progressive decline in WAS.
Eosinophils	May be elevated	Th2 skewing → eosinophilic inflammation (parallels elevated IgE)

Critical Exam Point – Pseudothrombocytopenia

The most common cause of thrombocytopenia in any setting is pseudo-thrombocytopenia → EDTA-dependent clumping of platelets ^[15]. Before diagnosing anything, always rule out pseudothrombocytopenia:

Check the peripheral blood smear for platelet clumps
If clumps seen → repeat CBC using a citrate tube instead of EDTA
In WAS, the thrombocytopenia is REAL — you will see genuinely small, sparse platelets on PBS without clumping.

Why we do it: To confirm thrombocytopenia is genuine (not pseudothrombocytopenia), assess platelet morphology, and exclude other diagnoses.

Finding	Interpretation
Small platelets	Confirms low MPV reading from CBC; small platelets are virtually pathognomonic for WAS
Reduced platelet number	Genuine thrombocytopenia (not EDTA artefact) ^[5]^[15]
No platelet clumps	Rules out pseudothrombocytopenia
No schistocytes	Rules out MAHA (HUS, TTP, DIC) — important to exclude in a child with thrombocytopenia + bloody diarrhoea
No blasts	Rules out leukaemia ^[5]
Eosinophilia	May be present — Th2 skewing
Lymphopenia (in older children)	Progressive T-cell decline

Why we do it: To exclude coexisting coagulopathy and to help differentiate from DIC (which would show prolonged PT/APTT with low fibrinogen and elevated D-dimer).

Parameter	Expected in WAS	Interpretation
PT	Normal	Extrinsic pathway intact ^[5]
APTT	Normal	Intrinsic pathway intact ^[5]
Fibrinogen	Normal	Not a consumption coagulopathy
D-dimer	Normal	Not DIC

In WAS, the bleeding diathesis is purely due to thrombocytopenia (quantitative platelet defect), not a coagulation factor problem. The clotting cascade is intact. This helps distinguish WAS from DIC (where PT, APTT, fibrinogen, and D-dimer are all deranged) ^[5].

3.2 Second-Line Immunological Investigations

Once CBC/MPV raises suspicion, proceed to a full immunological workup. This is typically done in a tertiary paediatric immunology centre (in Hong Kong: Queen Mary Hospital, Prince of Wales Hospital).

IgGAME — Low IgM → DOCK8, Wiskott-Aldrich syndrome, ataxia-telangiectasia ^[13]

Why we do it: The immunoglobulin pattern in WAS is characteristic and helps distinguish from other PIDs.

Immunoglobulin	Expected in WAS	Mechanism	Contrast with Other PIDs
IgM	Low ^[2]^[13]	Poor T-independent B-cell responses (IgM is the first-line antibody against polysaccharide antigens); accelerated IgM catabolism	In XLA: ALL Ig classes absent. In Hyper-IgM: IgM elevated, IgG/IgA low.
IgG	Normal or slightly low	Variable; may decline with disease progression	In XLA: severely reduced. In CVID: reduced.
IgA	Normal or elevated	Mucosal immune compensation	In XLA: absent.
IgE	Often elevated	Th2 skewing → class-switch to IgE	In Hyper-IgE syndrome: massively elevated (often > 2000 IU/mL). WAS elevation is usually more modest.

Paediatric interpretation note: Always compare Ig levels against age-matched reference ranges. Neonates have high IgG (passively acquired from mother) but low IgM and IgA. By 6–12 months, maternal IgG wanes. Infant-specific ranges must be used.

Why we do it: Isohemagglutinins are naturally occurring IgM antibodies against blood group A or B antigens. They are produced in response to gut bacterial polysaccharides (T-independent antigens) and serve as a simple, functional readout of IgM production capacity.

Finding in WAS	Interpretation
Absent or low titre	Confirms impaired IgM production and poor anti-polysaccharide responses

Only interpretable in patients who are blood group A, B, or O (not AB, who naturally lack isohemagglutinins). Also not reliable in infants < 6 months (maternal antibodies still present).

Vaccine responses ^[14] — specifically listed as a phenotypic investigation in the PID diagnostic approach.

Why we do it: To assess the functional capacity of the immune system to mount an antibody response. This goes beyond simply measuring Ig levels — it tells you whether the B cells and T-helper cells can cooperate to produce specific protective antibodies.

Vaccine Type	What It Tests	Expected in WAS
Protein antigens (e.g., tetanus, diphtheria)	T-dependent B-cell response (requires T-cell help)	May be normal or impaired (T-cell function variably affected)
Polysaccharide antigens (e.g., pneumococcal polysaccharide vaccine — Pneumovax 23)	T-independent B-cell response	Characteristically poor/absent — this is a hallmark of WAS. The inability to respond to polysaccharide antigens explains the vulnerability to encapsulated bacteria.

Only use unconjugated polysaccharide vaccines (e.g., Pneumovax 23) to test T-independent responses. Conjugate vaccines (e.g., PCV13) recruit T-cell help and bypass the T-independent pathway, so a response to PCV13 does not exclude WAS.

T, B, NK cell enumerations ^[14] Lymphocyte subset — low T cells (with or without low B and/or NK) → combined immunodeficiencies ^[13]

Why we do it: To characterise the type and severity of immune deficiency. This is done by flow cytometry using monoclonal antibodies against surface markers (CD3 for T cells, CD4 for T-helper, CD8 for cytotoxic T, CD19/CD20 for B cells, CD16/CD56 for NK cells).

Parameter	Expected in Classic WAS	Interpretation
CD3+ T cells	May be normal initially → progressive decline over years	WASp-deficient T cells undergo accelerated apoptosis; immune synapse dysfunction
CD4+ T-helper cells	Progressive decline	Impaired activation and survival
CD8+ T-cytotoxic cells	Variable	May be relatively preserved early
Naïve T cells (CD45RA+)	Reduced	Poor thymic output or accelerated peripheral turnover
CD19+ B cells	Usually normal in number	B cells are present but dysfunctional (poor antibody quality rather than absent B cells)
CD16+/CD56+ NK cells	Normal in number but impaired function	Number does not equal function — WASp is needed for NK cytotoxic granule polarisation

Paediatric normal values: T-cell and lymphocyte counts are physiologically higher in infancy than in adults (reflecting thymic activity). Always use age-matched reference ranges:

ALC in infants < 1 year: normal > 3000/μL ^[13]
ALC in children > 1 year: normal > 1000/μL ^[13]

Why we do it: Lymphocyte subset enumeration tells you how many T cells there are, but not how well they work. Proliferation assays stimulate T cells in vitro and measure their ability to divide.

Stimulus	What It Tests	Expected in WAS
Mitogens (PHA, ConA)	Non-specific T-cell proliferative capacity	Reduced (variably)
Antigens (Candida, tetanus)	Antigen-specific T-cell memory response	Often impaired
Anti-CD3/CD28	TCR-mediated activation	Impaired — reflects defective immune synapse formation due to absent WASp

3.3 Confirmatory Investigations — WASp-Specific

Why we do it: This is the most rapid and accessible confirmatory test for WAS. It directly assesses whether the WAS protein is present in the patient's immune cells.

Method: Peripheral blood lymphocytes are stained with an anti-WASp monoclonal antibody (intracellular staining, since WASp is a cytoplasmic protein) and analysed by flow cytometry.

Finding	Interpretation
WASp absent	Classic WAS (null mutation) → severe phenotype (score 3–5)
WASp reduced	X-linked thrombocytopenia (missense mutation) → milder phenotype (score 1–2)
WASp normal	WAS unlikely — reconsider diagnosis

Advantages: Fast (results within 1–2 days), widely available in tertiary centres, semi-quantitative.

Limitations: Cannot determine the exact mutation (need genetic testing for that); cannot distinguish between different types of null mutations; may be affected by recent blood transfusion (donor lymphocytes may express normal WASp, giving a falsely reassuring result).

Genetic testing has an important role in: Diagnosis (All cases), Family studies, Prognostication, Prenatal diagnosis ^[14]

Why we do it: This is the gold standard for definitive diagnosis. It identifies the exact pathogenic variant, which has implications for:

Confirming diagnosis — especially in atypical cases
Genotype-phenotype correlation — predicting severity
Family studies — carrier testing of maternal relatives
Prenatal diagnosis — for future pregnancies
Preimplantation genetic testing (PGT)

Methods used in Hong Kong:

Method	Description	When Used
Targeted Sanger sequencing of WAS gene	Direct sequencing of all 12 exons + splice sites	First-line when clinical suspicion is high
Next-generation sequencing (NGS) gene panel	Panel including WAS and other PID genes	When phenotype is atypical or multiple DDx possible
Whole-exome sequencing (WES)	Sequences all coding regions	When targeted approaches are negative; may detect novel mutations
Multiplex ligation-dependent probe amplification (MLPA) / CGH array	Detects large deletions/duplications	When sequencing is negative but WASp is absent (may miss large structural variants)

Interpretation of genetic results:

Mutation Type	WASp Status	Predicted Phenotype
Nonsense / frameshift / splice-site	Absent	Classic WAS (severe)
Missense in WH1 domain (hotspot: exons 1–3)	Reduced	XLT (mild) — most common XLT mutations
Missense elsewhere	Variable	Intermediate phenotype
Activating/gain-of-function in VCA domain	Constitutively active	X-linked neutropenia (XLN)
Variant of uncertain significance (VUS)	Uncertain	Requires functional studies + clinical correlation

3.4 Additional Supportive and Monitoring Investigations

These investigations are not for diagnosis per se but are essential for baseline assessment, complication screening, and management planning.

Why: Autoimmunity occurs in 40–70% of WAS patients and may present at any time.

Test	Purpose	Expected Findings
Direct Coombs test (DAT)	Screen for AIHA	Positive in autoimmune haemolytic anaemia
Reticulocyte count	Assess marrow response to anaemia	Elevated in haemolysis; low in marrow failure
Haemolysis markers (LDH, haptoglobin, bilirubin)	Confirm haemolysis	↑LDH, ↓haptoglobin, ↑unconjugated bilirubin in AIHA
Urinalysis	Screen for IgA nephropathy / vasculitis	Proteinuria, haematuria
ANA, anti-dsDNA	Screen for autoimmune disease	May be positive
Anti-platelet antibodies	Distinguish autoimmune component of thrombocytopenia	May be positive — contributes to platelet destruction beyond the intrinsic defect

Test	Purpose
Blood cultures	During febrile episodes
Viral serology/PCR (CMV, EBV, HSV, VZV, HIV)	Baseline and during suspected viral infections; EBV monitoring for lymphoproliferative disease risk
Fungal markers (beta-D-glucan, galactomannan)	If invasive fungal infection suspected
Stool culture + C. difficile toxin	For bloody diarrhoea workup
Chest X-ray	Baseline; assess thymic shadow (should be present in WAS, unlike SCID); monitor for pneumonia, lymphadenopathy

Investigation	Purpose
CXR	Baseline; look for thymic shadow (present in WAS), pneumonia, lymphadenopathy
Abdominal USS	Assess spleen size (splenomegaly from platelet trapping + chronic immune activation); liver (hepatomegaly); lymphadenopathy
CT head (urgent)	If any neurological symptoms → rule out intracranial haemorrhage (leading cause of mortality)

Why: If HSCT is planned (which it usually is for scores 3–5), HLA typing of the patient and potential family donors should be initiated early. This includes:

Patient HLA typing
Sibling HLA typing
Unrelated donor search (if no matched sibling)

HSCT is the definitive curative treatment for WAS ^[2]^[16]. HLA typing should begin as soon as diagnosis is confirmed.

When: Not routinely required for WAS diagnosis but may be performed if:

Need to exclude leukaemia or MDS (if pancytopenia or atypical features)
Assessing marrow cellularity before HSCT
Evaluating megakaryocyte morphology (in WAS: megakaryocytes present but may have abnormal morphology)

Stage	Investigations	Key Findings in WAS
Screening	CBC + MPV, PBS, coagulation profile	Thrombocytopenia + small platelets (MPV < 5 fL); normal clotting
Immunological	IgG/A/M/E, isohemagglutinins, vaccine responses, lymphocyte subsets, T-cell proliferation	Low IgM, ↑IgE, poor polysaccharide vaccine responses, progressive T-cell lymphopenia
Confirmatory	WASp expression (flow cytometry)	Absent or markedly reduced WASp
Definitive	WAS gene sequencing	Pathogenic mutation identified
Supportive	Autoimmune workup, infection screen, imaging, HLA typing	Assess complications; plan for HSCT

High Yield Summary — Diagnosis of WAS

The MPV is the most discriminating screening test: PLT low + MPV < 5 fL in a male infant = WAS until proven otherwise ^[13].
Immunoglobulin pattern: Low IgM is characteristic and flagged on GC lecture slides ^[13]. IgE often elevated. IgG normal or low.
WASp expression by flow cytometry is the fastest confirmatory test — absent WASp = classic WAS.
Genetic testing is required in all cases ^[14] — it confirms diagnosis, predicts severity, enables carrier testing and prenatal diagnosis.
Approach to PID diagnosis: Clinical history → Physical examination → Phenotypic investigations (IgG, IgA, IgM levels; Vaccine responses; T, B, NK cell enumerations; Lymphocyte subsets; Cell function) → Genetic testing ^[14].
Always rule out pseudothrombocytopenia (EDTA artefact) before pursuing further workup — check PBS for platelet clumps ^[15].
Paediatric normal values differ from adults: ALC < 3000/μL in infants < 1 year or < 1000/μL in children > 1 year is abnormal ^[13].

Active Recall - Diagnosis and Investigations of WAS

^[2] Senior notes: Jerry's immunodeficiencies.pdf (p2 — WAS tetrad, low IgM, low platelets, IUIS classification, treatment with HSCT) ^[5] Senior notes: Maksim Medicine Notes.pdf (p161 — platelet disorders DDx, CBC/PBS/coagulation investigations, EDTA causing platelet clumping) ^[13] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p50 — CBC findings: PLT low → WAS; Low IgM → WAS; ALC thresholds; lymphocyte subset interpretation; IgGAME patterns) ^[14] Lecture slides: Investigations of Imm Disorders 2025.pdf (p7, p10 — IUIS Tables, approach to PID diagnosis: phenotypic investigations including IgG/A/M, vaccine responses, T/B/NK enumerations, lymphocyte subsets, cell function; genetic testing roles) ^[15] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p3 — pseudothrombocytopenia from EDTA-dependent clumping, citrate correction) ^[16] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p29 — WAS as indication for HSCT, HSCT procedure rationale)

Before diving into specifics, understand the overarching management philosophy for WAS:

WAS is a progressive, life-threatening disease — without definitive treatment, median survival is < 20 years, with death from infection (~50%), haemorrhage (~25%), or malignancy (~25%).
The only curative treatment is haematopoietic stem cell transplantation (HSCT) ^[2]^[16] — this replaces the defective haematopoietic system with a normal one from a healthy donor. Gene therapy is emerging as an alternative curative approach.
Supportive care is essential to keep the child alive and well while awaiting or deciding on definitive treatment.
Severity scoring (Ochs/Zhu score 1–5) guides how aggressively to manage:
- Score 1–2 (XLT): May be managed conservatively with surveillance ± supportive care
- Score 3–5 (Classic WAS): HSCT strongly recommended

Indications for Allogeneic HSCT include: SCID, Wiskott-Aldrich ^[17]

This is explicitly listed on the GC 060 lecture slide as an established indication for allogeneic HSCT — extremely high yield for exams.

2. Immediate Measures at Diagnosis (All Patients)

These apply to every child diagnosed with WAS, regardless of severity score.

Why: WAS involves combined T-cell and B-cell dysfunction. Live attenuated vaccines (which rely on a competent immune system to contain the weakened pathogen) can cause disseminated infection in immunodeficient patients.

Live Vaccines to AVOID	Rationale
BCG	Risk of disseminated BCG-osis (similar to risk in SCID and CGD) ^[2]
MMR (measles, mumps, rubella)	Risk of vaccine-strain measles encephalitis
Varicella (VZV)	Risk of disseminated varicella
Rotavirus	Risk of prolonged/chronic rotavirus shedding and diarrhoea
Oral polio vaccine (OPV)	Risk of vaccine-associated paralytic polio (note: Hong Kong uses IPV, not OPV)
Yellow fever, live influenza (LAIV)	As above

Killed/inactivated vaccines (IPV, DTaP, hepatitis B, PCV13, influenza inactivated) are safe to administer but may produce a suboptimal immune response due to the underlying immunodeficiency. Despite this, they are still given because even a partial response offers some protection.

Begin HLA typing of the patient and all siblings immediately upon diagnosis ^[16]^[18]. If no matched sibling is available, initiate an unrelated donor search through registries (e.g., Hong Kong Bone Marrow Donor Registry, international registries via BMDW).

Arrange HLA typing for siblings if HSCT anticipated ^[18]

Confirm carrier status of the mother
Offer carrier testing to maternal aunts and sisters
Discuss prenatal/preimplantation genetic diagnosis for future pregnancies
Provide psychosocial support — this is a devastating diagnosis for families

All WAS patients requiring blood products should receive irradiated products to prevent transfusion-associated graft-versus-host disease (TA-GVHD).

Why: WAS patients have impaired T-cell function → cannot reject viable donor T-lymphocytes in transfused blood products → donor T cells can engraft and mount an immune response against the recipient's tissues → fatal TA-GVHD.

Irradiation of blood products is indicated for immunocompromised patients ^[19]. In emergency situations when irradiated products are unavailable, ask the blood bank for the oldest bag of blood — after 14 days of storage, lymphocytes should have died ^[19].

Irradiated: red cells, platelets, granulocytes
Does not need irradiation: FFP, cryoprecipitate (acellular products contain no viable lymphocytes)

High Yield — Irradiated Blood Products in WAS

WAS patients are immunocompromised and are therefore at risk of TA-GVHD. All cellular blood products (red cells, platelets) must be irradiated. This also applies to potential HSCT recipients. Communicate early with the blood bank so they can place an alert on the patient's CMS record ^[19].

3. Supportive Care (All Patients, Ongoing)

3.1 Management of Thrombocytopenia and Bleeding

The bleeding diathesis in WAS is due to microthrombocytopenia ^[2] — both quantitative reduction and qualitative dysfunction of platelets.

Indication: Active bleeding or prophylaxis before invasive procedures.

Situation	Platelet Threshold for Transfusion	Rationale
Active major bleeding (e.g., GI haemorrhage, ICH)	Transfuse regardless of count	Life-saving haemostasis
Before major surgery / invasive procedure	Aim platelet > 50,000/μL	Surgical haemostasis
Before minor procedure (e.g., LP)	Aim platelet > 20,000–50,000/μL	Depends on procedure risk
Prophylactic (no bleeding, no procedure)	Generally NOT given prophylactically	Repeated transfusions → alloimmunisation → platelet refractoriness; risk of TA-GVHD (use irradiated products); chronic transfusion dependence

Paediatric dosing: Platelet transfusion in children is typically 10–15 mL/kg of pooled platelet concentrate or 1 unit of apheresis platelets for older children. All products must be irradiated and CMV-negative (if potential HSCT recipient is CMV-seronegative) ^[18]^[19].

Important — Do Not Rely on Platelet Transfusion as Sole Strategy

Platelet transfusions in WAS provide only temporary benefit because:

Transfused platelets are normal-sized and functional but will be consumed/destroyed quickly (accelerated splenic clearance)
Repeated transfusions → alloimmunisation (anti-HLA/anti-HPA antibodies) → future platelet refractoriness
Risk of transfusion reactions and TA-GVHD (even with irradiation, risks not zero)

Platelet transfusion is for acute bleeding control, not long-term management.

Tranexamic acid (TXA) — an antifibrinolytic agent:

Mechanism: Inhibits plasminogen activation → prevents clot breakdown → stabilises whatever platelet plug is formed
Indication: Oral/mucosal bleeding (epistaxis, gingival bleeding), or as adjunct before dental procedures
Paediatric dose: 15–25 mg/kg/dose PO TDS (max 1.5 g/dose) or 10 mg/kg IV
Contraindications: Active thromboembolic disease, haematuria (risk of ureteric clot obstruction)

Avoid: Aspirin, NSAIDs (ibuprofen), any antiplatelet medications — these further impair already defective platelet function
Use paracetamol for analgesia/antipyresis instead

Eltrombopag (oral) and romiplostim (subcutaneous):

Mechanism: Stimulate the TPO receptor (c-Mpl) on megakaryocytes → increase platelet production
Role in WAS: Limited and off-label. Some case reports/small series show modest platelet count improvement, but the fundamental problem is not just reduced production — it's also defective platelet quality and accelerated destruction. TPO-RAs do not fix the actin cytoskeleton defect.
May be used as a bridge to HSCT in selected cases to reduce bleeding risk
Thrombopoietin receptor agonists e.g. eltrombopag and romiplostim are established treatments for refractory ITP ^[20], and their use has been extrapolated to WAS in selected cases

Rationale: The spleen is the primary site of destruction of the small, defective WAS platelets. Removing it can significantly improve platelet counts (often normalising them).

However: Splenectomy carries major risks in WAS:

Further immunocompromise: The spleen is a critical immunological organ for filtering encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis). Removing it in a child who already has impaired antibody responses (especially poor anti-polysaccharide responses) → dramatically increased risk of overwhelming post-splenectomy infection (OPSI) ^[21]
Risk of life-threatening infection from encapsulated bacteria → overwhelming post-splenectomy infection ^[21]

Current recommendation: Splenectomy is generally avoided in WAS in the modern era because HSCT is curative and addresses both the thrombocytopenia AND the immunodeficiency. Splenectomy was historically performed but is now considered only in:

Very selected cases with life-threatening bleeding refractory to all other measures
When HSCT is not available or feasible

Splenectomy in paediatric patients has worse immune consequences — we try to delay it as much as possible ^[21].

If splenectomy is performed, mandatory post-splenectomy precautions include:

Pre-splenectomy vaccination (PCV13/PPSV23, MenACWY, Hib) — though response may be poor in WAS
Lifelong antibiotic prophylaxis (phenoxymethylpenicillin / penicillin V)
Medic-alert bracelet
Urgent medical attention for any fever

IVIG / SCIG is the established treatment for antibody deficiency in PIDs ^[2]

Why: WAS patients have impaired antibody production (low IgM, poor vaccine responses, especially to polysaccharide antigens) → passive replacement with pooled donor IgG provides broad-spectrum antibody protection.

Route	Preparation	Dosing (Paediatric)	Frequency	Advantages	Disadvantages
IVIG (intravenous)	Pooled human IgG	400–600 mg/kg/dose	Every 3–4 weeks	Rapid peak levels; administered in hospital/day-care	Requires IV access; infusion reactions; time in hospital
SCIG (subcutaneous)	Pooled human IgG	100–200 mg/kg/week (equivalent total monthly dose)	Weekly or biweekly	Home-based; fewer systemic reactions; more stable serum IgG levels	Requires training; local site reactions; multiple sites may be needed

Target trough IgG level: > 8 g/L (some centres aim > 10 g/L in patients with recurrent infections).

Why does IVIG help even though IgG may be normal?

Even if the total IgG level is within the normal range, the functional quality of WAS-patient-produced IgG is poor (reduced affinity, impaired responses to specific pathogens). Replacement IgG from healthy donors provides functional, protective antibodies against common pathogens.

Agent	Target Pathogens	Indication	Paediatric Dose
Co-trimoxazole (TMP-SMX / Septrin)	Pneumocystis jirovecii (PJP)	Prophylaxis against PJP in all classic WAS patients (T-cell deficiency)	TMP 5 mg/kg/day (max 160 mg) PO divided BD, 3 days per week
Aciclovir / Valaciclovir	HSV, VZV	Prophylaxis if history of herpetic infections or in severely immunocompromised patients	Aciclovir 10–20 mg/kg/dose PO TDS (age-dependent)
Antifungal (fluconazole / itraconazole)	Candida, moulds	If recurrent fungal infections or severe immunodeficiency	Fluconazole 3–6 mg/kg/day PO
Penicillin V	Encapsulated bacteria	If post-splenectomy or functionally asplenic	125 mg PO BD (< 5 years); 250 mg PO BD (≥ 5 years)

Septrin prophylaxis is used for PJP prevention in immunocompromised patients post-chemotherapy or with T-cell deficiency ^[22]

The eczema in WAS is managed similarly to atopic dermatitis, but tends to be more severe and refractory:

Step	Treatment	Notes
Step 1: Emollients	Liberal emollient application (e.g., aqueous cream, paraffin-based) multiple times daily	Restores skin barrier; reduces transepidermal water loss
Step 2: Topical corticosteroids	Low-to-mid potency (e.g., 1% hydrocortisone for face; 0.1% mometasone for body)	Step up potency as needed; avoid prolonged use on thin skin (face, flexures)
Step 3: Topical calcineurin inhibitors	Tacrolimus 0.03% ointment (children 2–15 years)	Steroid-sparing for face/flexures; avoid in active infection
Step 4: Systemic immunosuppression	Reserved for severe, refractory cases — discuss with immunologist	Caution: further immunosuppression in an already immunodeficient child
Infection control	Bleach baths (dilute sodium hypochlorite 0.005%); topical antiseptics (chlorhexidine); antibiotics for secondary infection	S. aureus colonisation exacerbates eczema; treat superinfection promptly
Wet wraps	For acute flares in young children	Enhances absorption of topical steroids; provides comfort

Caution: Unlike idiopathic atopic dermatitis, the eczema of WAS will only be completely cured by HSCT (which replaces the dysfunctional immune system). Topical/supportive treatment controls symptoms but does not address the root cause.

Febrile episodes: Treat as potentially serious — low threshold for blood cultures, empirical broad-spectrum antibiotics (e.g., IV ceftriaxone or piperacillin-tazobactam depending on local protocol)
Neutropenic fever protocol: If the child develops neutropenia (which can occur with progressive disease or post-HSCT), follow standard neutropenic sepsis protocols — immediate empirical broad spectrum antibiotics for neutropenic sepsis ^[17]
Viral infections: Active monitoring for CMV, EBV (especially given lymphoma risk); treatment with ganciclovir/valganciclovir for CMV; rituximab ± chemotherapy for EBV-driven lymphoproliferative disease

4. Definitive Curative Treatment

4.1 Haematopoietic Stem Cell Transplantation (HSCT)

Indications for Allogeneic HSCT: SCID, Wiskott-Aldrich, Thalassemia major, Aplastic anemia, Fanconi's anemia ^[17]

Inborn errors of immunity / primary immunodeficiencies → SCID, Wiskott-Aldrich — listed as HSCT indications ^[16]

HSCT is the gold standard curative treatment for WAS. It replaces the defective WASp-negative haematopoietic system with a normal WASp-positive one from the donor.

Let me walk through the rationale, following the HSCT procedure steps taught in the GC lectures:

Conditioning → Donor graft → Immunosuppression ^[16]

Step	What Happens	Why in WAS
Conditioning	High-dose chemotherapy ± radiotherapy to eradicate the recipient's bone marrow ^[16]	Destroys the WASp-deficient haematopoietic stem cells (HSCs); creates "space" in the marrow for donor HSCs to engraft; also immunosuppresses the recipient to prevent graft rejection
Donor graft	Infusion of donor HSCs (bone marrow, PBSC, or cord blood) ^[16]	Donor HSCs carry normal WAS genes → they engraft and produce WASp-positive T cells, B cells, NK cells, platelets, and phagocytes → all arms of immunity are reconstituted; platelets become normal in number AND size
Immunosuppression	Post-transplant immunosuppressive drugs to prevent GVHD ^[16]	Donor immune cells may recognise the recipient's tissues as foreign → GVHD. Immunosuppressive agents (e.g., ciclosporin, methotrexate, mycophenolate) are used to prevent this

2–3 weeks of cytopenic phase after giving stem cells — time needed for engraftment (recovery of neutrophils and platelets). Patient is in an extremely weak phase, requires supportive care and isolation ^[16]

The outcome of HSCT depends heavily on the donor source. In order of preference:

Priority	Donor Type	HLA Match	Expected Outcome	Notes
1st	HLA-matched sibling donor (MSD)	10/10	Best: OS > 90%	Gold standard; lowest GVHD risk
2nd	HLA-matched unrelated donor (MUD)	10/10 or 9/10	Very good: OS 80–90%	Slightly higher GVHD risk; longer search time
3rd	Haploidentical family donor	5/10 (parent or sibling)	Good with modern techniques: OS 70–85%	T-cell depletion or post-transplant cyclophosphamide reduces GVHD; readily available
4th	Unrelated cord blood	≥ 4/6	Good: OS 70–80%	Lower GVHD risk; smaller cell dose → slower engraftment

Paediatric considerations:

In children, bone marrow is the preferred stem cell source (lower GVHD risk than PBSC)
For cord blood transplant, the cord blood unit must contain an adequate cell dose relative to the child's body weight (> 3 × 10^7 TNC/kg)

Type	Intensity	Drugs Commonly Used	When Used
Myeloablative conditioning (MAC)	High	Busulfan + cyclophosphamide ± fludarabine	Standard for WAS; ensures full donor chimerism
Reduced-intensity conditioning (RIC)	Lower	Fludarabine + melphalan or treosulfan	For patients with significant comorbidities or organ damage; may result in mixed chimerism

Why full myeloablation matters in WAS: Unlike some conditions where mixed chimerism is acceptable, WAS patients ideally need high donor chimerism — because even a small proportion of residual WASp-deficient cells (especially platelets and megakaryocytes) can perpetuate thrombocytopenia. Full donor myeloid engraftment → normalisation of platelet count and size.

Factor	Impact on Outcome
Age at transplant	Younger is better (< 5 years, ideally < 2 years) — less accumulated organ damage, fewer autoimmune complications, lower malignancy risk
Donor match	MSD > MUD > Haplo/Cord — GVHD and graft failure risk increases with mismatch
Severity score	Score 3–5 have more indication but also more comorbidities — transplant earlier before complications accumulate
Pre-existing autoimmunity	Associated with higher HSCT morbidity
Pre-existing infections	Active infections should be controlled before HSCT

Overall survival with HSCT: > 85–90% with MSD; 75–85% with MUD/alternative donors in the modern era (2020s data).

Parameter	What to Monitor	Why
Engraftment	Neutrophil recovery (ANC > 500/μL for 3 consecutive days); platelet recovery (> 20,000/μL without transfusion)	Confirms donor cells are producing blood cells
Chimerism analysis	PCR-based donor vs recipient DNA quantification	Full donor chimerism preferred; mixed chimerism may require donor lymphocyte infusion (DLI)
GVHD	Skin (rash), gut (diarrhoea), liver (jaundice, elevated LFTs)	Acute GVHD (< 100 days); chronic GVHD (> 100 days)
Immune reconstitution	Lymphocyte subsets, Ig levels, vaccine responses	Full immune recovery takes 12–24 months; re-vaccination required
Infections	CMV, EBV PCR monitoring; fungal markers	Immunosuppression → infection risk especially in first 6–12 months
Late effects	Growth, endocrine function, fertility, secondary malignancy	Conditioning regimen toxicity; monitor long-term in survivorship clinic

Complication	Mechanism	Management
Graft-versus-host disease (GVHD)	Donor T cells attack recipient tissues (skin, gut, liver)	Prophylaxis: ciclosporin ± methotrexate/mycophenolate; Treatment: systemic corticosteroids ± additional immunosuppression
Graft failure	Recipient immune system rejects donor cells; inadequate conditioning	Donor lymphocyte infusion; second transplant
Infections	Post-conditioning immunosuppression	Antibacterial, antifungal, antiviral prophylaxis and monitoring ^[17]^[22]
Veno-occlusive disease / sinusoidal obstruction syndrome	Conditioning-induced hepatic endothelial damage	Defibrotide; supportive care
Late effects	Conditioning toxicity: gonadal failure, growth impairment, secondary malignancy	Long-term follow-up in survivorship clinic

Gene therapy is an exciting emerging curative option for WAS, particularly relevant for patients who lack a suitable HSCT donor.

Principle: The patient's own HSCs are harvested, genetically corrected ex vivo using a lentiviral vector carrying a functional WAS gene, and then reinfused after conditioning. This results in autologous transplantation of genetically corrected cells → no risk of GVHD (since the cells are self).

Aspect	Details
Vector	Lentiviral vector (self-inactivating) carrying functional WAS cDNA under the endogenous WAS promoter
Advantages	No GVHD risk; no need for donor; can be used when no matched donor available
Disadvantages / Risks	Insertional mutagenesis (though much lower with modern SIN lentiviral vectors than early retroviral vectors); variable and sometimes incomplete correction; not yet universally available
Current status (2025–2026)	Clinical trials in Europe (Milan, London, Paris, Boston) have shown promising results with sustained multilineage correction; some patients have achieved platelet normalisation and immune reconstitution; now approaching licensed therapy status in EU/US
Relevance to Hong Kong	Not yet routinely available in Hong Kong; patients may be referred to international centres for gene therapy trials

Score	Phenotype	Management Approach
1	XLT — intermittent thrombocytopenia only	Surveillance; avoid contact sports; platelet transfusion PRN; IVIG not routinely needed; consider HSCT only if progression
2	XLT — persistent thrombocytopenia + mild eczema	Surveillance + supportive care (emollients, topical steroids); IVIG if recurrent infections; platelet transfusion PRN; HSCT if progression
3	WAS — eczema responsive to therapy + recurrent infections	HSCT recommended; IVIG replacement; antimicrobial prophylaxis; eczema management; platelet support
4	WAS — severe eczema + life-threatening infections	HSCT urgent; intensive supportive care; IVIG; broad antimicrobial prophylaxis; may need hospitalisation for infection management
5	WAS + autoimmunity and/or malignancy	HSCT urgent (if feasible after treating active autoimmunity/malignancy); immunosuppression for autoimmune complications; chemotherapy for malignancy; complex multidisciplinary management

6. Special Paediatric Considerations

Plot weight, height/length, and head circumference on age-appropriate growth charts at every visit
Failure to thrive is common — chronic infections, bloody diarrhoea, and inflammation all impair growth
Nutritional support: Ensure adequate caloric intake; may need dietitian input; iron supplementation for chronic blood loss (monitor ferritin to avoid overload with repeated transfusions)

Chronic illness in infancy can impact neurodevelopment — regular developmental screening
ICH (even subclinical) can cause developmental delay — maintain high vigilance
Psychomotor development is usually normal in WAS (unlike some other PIDs like ataxia-telangiectasia)

Vaccine Type	Recommendation
Killed/inactivated vaccines	Give as per standard Hong Kong childhood schedule; accept suboptimal response
Live vaccines	CONTRAINDICATED until immune reconstitution confirmed post-HSCT
Post-HSCT re-vaccination	Start 6–12 months post-HSCT with killed vaccines; live vaccines (MMR, varicella) only after confirmed immune reconstitution (adequate T-cell function, off immunosuppression for ≥ 6 months)

Parent support groups: Connect families with PID support organisations (e.g., Jeffrey Modell Foundation, IPOPI)
School liaison: Ensure school understands the child's condition, infection precautions, and bleeding risk
Adolescent transition: For survivors post-HSCT, plan transition to adult immunology services
Sibling screening: All male siblings should be tested; all female siblings should be offered carrier testing

Informed consent from parents/legal guardians — explain curative intent, risks of HSCT (GVHD, graft failure, infection, late effects, mortality risk ~5–15%), and alternative of conservative management
Assent from the child when developmentally appropriate (typically > 7 years in Hong Kong)
For complex decisions (e.g., haploidentical transplant vs gene therapy trial), multidisciplinary team meeting + clinical ethics input

High Yield Summary — Management of WAS

HSCT is the only curative treatment for WAS — indicated for clinical severity score ≥ 3. Listed on GC 060 lecture slide as an established indication for allogeneic HSCT ^[17].
Donor preference: Matched sibling donor > Matched unrelated donor > Haploidentical/Cord blood.
HSCT procedure: Conditioning (high-dose chemo/radio to eradicate diseased marrow) → Donor graft (replace with healthy HSCs) → Immunosuppression (prevent GVHD) ^[16].
Supportive care for ALL patients: Avoid live vaccines; IVIG replacement; antimicrobial prophylaxis (co-trimoxazole for PJP); eczema management; platelet transfusion for acute bleeding (irradiated products); avoidance of NSAIDs/aspirin.
Splenectomy is generally avoided in WAS — improves platelet count but dramatically worsens infection risk in a child who already has poor antibody responses.
Gene therapy is emerging as a curative option, especially for patients lacking suitable HSCT donors.
Irradiated blood products are mandatory for all WAS patients to prevent TA-GVHD ^[19].
Transplant early — outcomes are better when HSCT is performed at younger age (< 5 years, ideally < 2 years) before complications accumulate.

Active Recall - Management of WAS

^[2] Senior notes: Jerry's immunodeficiencies.pdf (p2 — WAS tetrad, low IgM, treatment with HSCT, IVIG/SCIG for antibody deficiency) ^[16] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p29 — WAS as HSCT indication; HSCT procedure: conditioning, donor graft, immunosuppression; BMT vs PBSCT vs HSCT terminology; cytopenic phase and supportive care) ^[17] Lecture slides: GC 060. High white cell count.pdf (p38 — Indications for Allogeneic HSCT including SCID, Wiskott-Aldrich; p11 — Supportive treatment including neutropenic sepsis management, platelet transfusions, antifungal prophylaxis) ^[18] Senior notes: Ryan Ho Haemtology.pdf (p52 — Arrange HLA typing for siblings if HSCT anticipated; CMV-negative blood for potential HSCT recipients; general management of haematological malignancies including blood product support) ^[19] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p22 — Indications for irradiated blood products in immunocompromised patients; oldest bag of blood in emergency; TA-GVHD prevention) ^[20] Senior notes: Block A - Abnormal bleeding after tooth extraction_ bleeding tendency; thrombocytopenia.pdf (p11 — Treatment of platelet disorders including platelet transfusion, steroids, IVIG, TPO-RAs) ^[21] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p19 — Splenectomy indications and complications; OPSI from encapsulated bacteria; paediatric considerations; post-splenectomy CBC changes) ^[22] Lecture slides: Block C - A child with cancer_ paediatric cancers.pdf (p14 — Supportive care: blood product support, treatment of infection including septrin prophylaxis for PCP, tumour lysis syndrome)

WAS is not simply an immunodeficiency — it is a disease that attacks children on three fronts simultaneously, and the complications reflect this:

Bleeding complications — from microthrombocytopenia
Infectious complications — from combined immunodeficiency
Immune dysregulation complications — autoimmunity and malignancy from defective immune surveillance and tolerance

Without definitive treatment (HSCT or gene therapy), these complications are progressive — they worsen with age as T-cell numbers decline, autoantibodies accumulate, and cumulative organ damage accrues. Understanding each complication from first principles (i.e., tracing it back to the absent WASp → defective actin cytoskeleton → specific cellular dysfunction) is the key to both exam success and clinical management.

Remember that immunodeficiency is not just infection susceptibility — also increased risk for autoimmune diseases, malignancy etc. ^[2]

Implications of X-linked pattern of inheritance — increased risk of infections, autoimmune (especially neutropenia), lymphoproliferative/malignant complications (especially lymphoma/GI involvement) ^[23]

1. Haemorrhagic Complications

The bleeding in WAS is fundamentally due to microthrombocytopenia — platelets that are both low in number AND small in size ^[2]. The mechanism is twofold:

Quantitative defect: Reduced platelet count (typically 10,000–50,000/μL)
Qualitative defect: Even the platelets that are present are dysfunctional — WASp is needed for actin-dependent platelet shape change, granule release, and clot retraction

Both platelet and coagulation problems can cause intracranial haemorrhages — cannot say one is more deadly than the other ^[20]

Complication	Mechanism	Clinical Features	Paediatric Significance
Petechiae and purpura	Capillary bleeding without adequate platelet plug	Non-blanching spots/patches on skin and mucous membranes; often first presentation in neonates	Very common — often noticed by parents in the first weeks of life
Epistaxis	Mucosal bleeding from rich nasal vascular plexus (Kiesselbach plexus)	Recurrent nosebleeds, sometimes prolonged	Common in toddlers; may be severe enough to require nasal packing or transfusion
Oral/gingival bleeding	Mucosal bleeding; exacerbated by teething in infants	Bleeding with tooth eruption, dental procedures, or minor oral trauma	Dental procedures require platelet support and antifibrinolytics (tranexamic acid)
Bloody diarrhoea (haematochezia)	GI mucosal bleeding due to thrombocytopenia; may be compounded by autoimmune enteropathy	Part of the WAS tetrad ^[2]; fresh blood in stools; can cause iron deficiency anaemia	Often mistaken for cow's milk protein allergy, infectious colitis, or HUS in infants
Gastrointestinal haemorrhage	Diffuse mucosal oozing or discrete ulcers from impaired haemostasis ± autoimmune colitis	Melena (upper GI) or haematochezia (lower GI); may be massive	Can be life-threatening; may require endoscopy, platelet transfusion, and sometimes surgical intervention
Intracranial haemorrhage (ICH)	Spontaneous bleeding into brain parenchyma, subdural, or subarachnoid space when platelets are critically low (< 10,000–20,000/μL)	Bulging fontanelle (infants), altered consciousness, seizures, focal neurological deficits, apnoea	Leading cause of death in WAS — accounts for approximately 20–25% of mortality. Any neurological change warrants urgent CT head and platelet transfusion
Post-circumcision bleeding	Inadequate haemostasis after surgical wound	Prolonged oozing or frank bleeding from circumcision site	May be the presenting feature in neonates; always check CBC before circumcision in any infant with FHx of WAS
Post-traumatic bleeding	Impaired primary haemostasis after minor trauma	Excessive bruising, haematomas from minor falls	Children are inherently at risk for minor trauma (play, crawling, toddling); advise parents on injury prevention

Critical — Intracranial Haemorrhage

ICH is the single most feared acute complication of WAS. It can occur spontaneously when platelets drop below 10,000–20,000/μL. In infants, signs may be subtle — irritability, poor feeding, vomiting, tense fontanelle, seizures. Maintain a very low threshold for CT head in any WAS child with neurological changes. This is a medical emergency requiring immediate platelet transfusion (irradiated), urgent neurosurgical consultation, and often ICU admission.

Chronic mucosal bleeding (GI, nasal) → ongoing iron loss → iron deficiency anaemia superimposed on the underlying thrombocytopenia. This requires:

Regular monitoring of iron studies (ferritin, serum iron, TIBC)
Oral iron supplementation when needed (paediatric dose: 3–6 mg/kg/day of elemental iron)
Caution: If the child is also receiving repeated platelet/red cell transfusions, there is a paradoxical risk of iron overload from transfusional iron (each unit of packed red cells contains ~200 mg iron). Monitor ferritin and consider chelation (deferasirox preferred in paediatrics for oral convenience) if ferritin exceeds 1000 μg/L.

2. Infectious Complications

WAS causes a combined immunodeficiency affecting T cells, B cells, NK cells, and innate immunity:

Immune Component	Defect in WAS	Consequence
T cells	Impaired immune synapse formation, progressive lymphopenia, accelerated apoptosis	Vulnerability to intracellular pathogens: viruses (CMV, EBV, HSV, VZV), fungi (PJP, Candida), mycobacteria
B cells	Poor antibody quality (especially anti-polysaccharide IgM); low IgM ^[2]^[13]	Vulnerability to encapsulated bacteria: S. pneumoniae, H. influenzae, N. meningitidis
NK cells	Impaired cytotoxic granule polarisation	Reduced clearance of virus-infected cells and tumour cells
Phagocytes	Impaired chemotaxis and migration	Delayed arrival at infection sites; poor bacterial clearance

Infection Type	Common Pathogens	Clinical Presentation	Why in WAS
Recurrent otitis media	S. pneumoniae, H. influenzae, M. catarrhalis	Ear pain, fever, otorrhoea; ≥ 4 episodes/year typical	Poor anti-polysaccharide antibody responses (low IgM) → poor defence against encapsulated bacteria
Sinopulmonary infections	S. pneumoniae, H. influenzae, S. aureus	Recurrent sinusitis, pneumonia; may lead to bronchiectasis	Antibody deficiency + impaired mucosal immunity
Skin infections	S. aureus, HSV, molluscum contagiosum	Cellulitis, impetigo, eczema herpeticum (disseminated HSV in eczematous skin), widespread molluscum	Broken skin barrier (eczema) + impaired cellular immunity
Eczema herpeticum	HSV-1 or HSV-2	Widespread vesicular/pustular eruption on eczematous skin; can be life-threatening with viraemia	T-cell deficiency → inability to contain HSV replication in damaged skin; requires urgent IV aciclovir
Pneumocystis jirovecii pneumonia (PJP)	P. jirovecii	Progressive dyspnoea, dry cough, hypoxia; bilateral interstitial infiltrates on CXR	T-cell deficiency (PJP is the classic opportunistic infection of T-cell-deficient states) → co-trimoxazole prophylaxis mandatory
Invasive fungal infections	Candida, Aspergillus	Oral thrush, oesophageal candidiasis, invasive aspergillosis (lung)	Combined immune deficiency; particularly after HSCT conditioning
Viral infections	CMV, EBV, VZV, RSV	Disseminated or severe primary infections; chronic viral shedding; EBV → lymphoproliferative disease	Impaired T-cell and NK-cell mediated viral clearance
BCG-osis (if BCG vaccine given)	M. bovis BCG	Local or disseminated BCG infection	Live BCG vaccine in an immunodeficient child → the attenuated mycobacterium disseminates. This is why live vaccines are contraindicated ^[2]
Sepsis / meningitis	Encapsulated bacteria, Gram-negatives	Fulminant illness with high mortality	Antibody deficiency + complement dysfunction + splenic overwork

Infections (especially cryptosporidium, a protozoan parasite), autoimmune (especially neutropenia), lymphoproliferative/malignant complications (especially lymphoma/GI involvement) ^[23]

Sequela	Mechanism	Long-term Impact
Bronchiectasis	Repeated lower respiratory infections → chronic airway inflammation → permanent bronchial dilatation	Chronic productive cough, recurrent exacerbations; may require long-term physiotherapy and prophylactic antibiotics
Chronic lung disease	PJP, recurrent pneumonia, post-infectious fibrosis	Restrictive or obstructive lung disease; may complicate HSCT conditioning
Chronic diarrhoea / malabsorption	Chronic GI infections (Cryptosporidium, Giardia, CMV colitis) + autoimmune enteropathy	Failure to thrive; micronutrient deficiencies; may require parenteral nutrition

3. Autoimmune Complications

Autoimmunity is a major and often underappreciated complication of WAS, occurring in 40–72% of patients with classic WAS. The mechanism:

Defective regulatory T cells (Tregs): WASp is essential for Treg-mediated suppressive function. Without WASp → Tregs cannot form proper immune synapses → loss of peripheral tolerance → self-reactive T and B cells escape control
Impaired clearance of apoptotic cells: WASp-deficient phagocytes have impaired cytoskeletal-dependent phagocytic function → apoptotic cell debris accumulates → serves as a source of autoantigens → drives autoantibody production
Chronic immune activation: Persistent infections → chronic inflammatory milieu → polyclonal B-cell activation → autoantibody generation

The development of autoimmunity is a poor prognostic sign in WAS and elevates the clinical severity score to 5 — the highest level, necessitating urgent consideration of HSCT.

Autoimmune Complication	Frequency	Mechanism	Clinical Features	Paediatric Management
Autoimmune haemolytic anaemia (AIHA)	Most common (~30–40%)	Autoantibodies (usually warm IgG) against red cell surface antigens → complement-mediated and/or splenic destruction	Pallor, jaundice, dark urine (haemoglobinuria), fatigue; positive DAT (Coombs test); elevated LDH, low haptoglobin, elevated unconjugated bilirubin, reticulocytosis	Corticosteroids (prednisolone 1–2 mg/kg/day); IVIG; rituximab for refractory cases; avoid splenectomy if possible
Autoimmune neutropenia	~15–25%	Autoantibodies against neutrophil surface antigens → accelerated neutrophil destruction	Recurrent bacterial infections disproportionate to the T/B-cell defect; isolated neutropenia on CBC	G-CSF; corticosteroids; IVIG
Autoimmune thrombocytopenia (ITP-like)	Superimposed on intrinsic thrombocytopenia	Anti-platelet autoantibodies (anti-GPIIb/IIIa, anti-GPIb/IX) → further accelerated platelet destruction beyond the baseline defect	Worsening thrombocytopenia below baseline; increased bleeding	Difficult to manage — steroids, IVIG, rituximab; this complicates the already low platelets
Evans syndrome	~5–10%	Concurrent AIHA + autoimmune thrombocytopenia (and sometimes autoimmune neutropenia)	Combined cytopenias; very serious	Aggressive immunosuppression; may require emergent HSCT
IgA nephropathy / vasculitis	~10–20%	IgA immune complex deposition in glomerular mesangium or small vessel walls	Haematuria, proteinuria, hypertension (nephropathy); palpable purpura, arthralgia (HSP-like vasculitis)	Urinalysis screening at each visit; ACEi/ARB for proteinuria; immunosuppression for severe nephritis
Inflammatory bowel disease-like colitis	~10%	Autoimmune-mediated intestinal inflammation; may also relate to chronic infection-driven inflammation	Bloody diarrhoea (overlapping with thrombocytopenia-related GI bleeding), abdominal pain, malabsorption	Difficult to distinguish from thrombocytopenia-related bleeding; may require endoscopy; treated with corticosteroids, aminosalicylates, or biologics
Autoimmune arthritis	~5%	Autoantibody-mediated joint inflammation	Joint swelling, pain, stiffness	NSAIDs (caution: avoid in severe thrombocytopenia due to antiplatelet effect); low-dose steroids
Cerebral vasculitis	Rare but devastating	Autoimmune inflammation of cerebral blood vessels → ischaemia/haemorrhage	Headache, seizures, focal neurological deficits, stroke-like presentations	MRI/MRA brain; high-dose corticosteroids; cyclophosphamide for severe cases; may be confounded by ICH from thrombocytopenia

Clinical Pearl — The 'Second Hit' of Autoimmune Thrombocytopenia

WAS patients already have intrinsic microthrombocytopenia. When autoimmune thrombocytopenia develops on top of this (anti-platelet autoantibodies), the platelet count can drop to critically low levels (< 5,000/μL), dramatically increasing the risk of fatal ICH. Clinically, you should suspect this "second hit" if a WAS patient's baseline platelet count suddenly drops further without another explanation (e.g., sepsis, DIC). Anti-platelet antibody testing and a trial of IVIG or corticosteroids may help.

4. Malignant Complications

WAS carries a 13–22% lifetime risk of malignancy, with risk increasing with age. The mechanism:

Impaired immune surveillance: WASp-deficient NK cells and cytotoxic T cells cannot effectively kill tumour cells (defective actin-dependent cytotoxic granule polarisation)
Chronic EBV infection: WAS patients cannot adequately control EBV → persistent EBV-driven B-cell proliferation → lymphoproliferative disease → frank lymphoma
Chronic immune stimulation: Persistent infections and autoimmunity → polyclonal lymphoproliferation → increased risk of clonal evolution and malignant transformation
Genomic instability: Some evidence that WASp deficiency impairs DNA damage responses in haematopoietic cells

Lymphoproliferative/malignant complications (especially lymphoma/GI involvement) ^[23]

Malignancy	Frequency	Mechanism	Clinical Features	Prognosis
EBV-driven lymphoproliferative disease	Most common malignant complication	Uncontrolled EBV replication → polyclonal B-cell expansion → monoclonal transformation	Lymphadenopathy, hepatosplenomegaly, fever, weight loss; elevated EBV viral load by PCR	May respond to rituximab ± chemotherapy; HSCT may be needed
Non-Hodgkin lymphoma (NHL)	Most common frank lymphoma	EBV-driven B-cell lymphoma (DLBCL, Burkitt-like); less commonly T-cell lymphoma	Rapidly enlarging lymph nodes, extranodal disease (GI tract common), B-symptoms	Poor prognosis if advanced; treatment with chemotherapy ± rituximab; HSCT if in remission
Leukaemia	Less common than lymphoma	Chronic immune stimulation + genomic instability → clonal haematopoietic malignancy	Pancytopenia, bone pain, hepatosplenomegaly, blasts on PBS/BM	Standard leukaemia protocols adapted for immunodeficiency; HSCT after remission
Myelodysplastic syndrome (MDS)	Rare	Bone marrow stress from chronic cytopenias + genomic instability	Worsening cytopenias, dysplastic features on BM	HSCT is definitive treatment

Monitoring	Frequency	Rationale
EBV viral load (PCR)	Every 3–6 months	Early detection of EBV reactivation → preemptive treatment before lymphoproliferative disease develops
Physical exam for lymphadenopathy	Every visit	Rapidly enlarging lymph nodes may signal lymphoma
CBC with differential	Every 3–6 months	Monitor for worsening cytopenias, new blasts, or dysplastic features
LDH	As needed	Non-specific tumour marker; elevated in lymphoma and haemolysis
Imaging (USS abdomen, CT if indicated)	As clinically indicated	Assess for deep lymphadenopathy, splenomegaly, extranodal disease

5. Complications of Treatment

Since HSCT is the curative treatment for WAS, its complications are directly relevant.

Complications of HSCT ^[24]:

Timing	Complication	Mechanism	Clinical Features
Early (< 1 year)	Cytopenia-related: anaemia, bleeding, neutropenic infections ^[24]	Post-conditioning bone marrow aplasia during engraftment	Transfusion dependence; life-threatening infections (bacterial and fungal); bleeding (26% in first year) ^[24]
	Oral/non-oral mucositis ^[24]	Conditioning regimen toxicity to rapidly dividing mucosal cells	Severe oral pain, dysphagia, diarrhoea, abdominal pain; may require TPN
	Veno-occlusive disease (VOD) / sinusoidal obstruction syndrome ^[24]	Conditioning damages hepatic venous endothelium → sinusoidal thrombosis → hepatic congestion	Painful hepatomegaly, ascites, jaundice ± fulminant liver failure ^[24]; Rx: defibrotide + supportive
	Acute graft-versus-host disease (aGVHD) ^[24]	Donor T cells recognise recipient tissues as foreign → immune attack on skin, gut, liver	Skin rash (maculopapular), profuse watery/bloody diarrhoea, cholestatic jaundice; grading I–IV
	Graft failure/rejection	Residual recipient immune system rejects donor cells; or inadequate conditioning	Failure to engraft (persistent pancytopenia); may require second transplant or donor lymphocyte infusion
Late (> 1 year)	Chronic graft-versus-host disease (cGVHD) ^[24]	Ongoing donor immune cell reactivity against recipient tissues	Sclerodermatous skin changes, sicca syndrome, bronchiolitis obliterans, liver dysfunction, joint contractures
	Second malignancy ^[24]	Conditioning-related DNA damage + chronic immunosuppression	Post-transplant lymphoproliferative disease (PTLD) — EBV-related B-cell lymphoma; post-treatment MDS/AML; solid organ tumours (especially SCC of skin/oral cavity) ^[24]^[25]
	Endocrine dysfunction ^[24]	Conditioning regimen (especially total body irradiation) toxicity to endocrine organs	T2DM, hypothyroidism, hypogonadism, infertility, osteoporosis ^[24]
	Cardiovascular disease ^[24]	Metabolic effects of immunosuppressants + co-incident CV risk factors + cGVHD	Most common cause of non-relapse morbidity/mortality; 5% at 5 years, 9% at 15 years post-HSCT ^[24]
	Cataracts	Total body irradiation damage to the lens	Visual impairment; requires ophthalmological screening ^[24]
	Infertility	Gonadotoxic conditioning agents (alkylating agents, TBI)	Discuss fertility preservation before HSCT where age-appropriate (semen cryopreservation in adolescent boys; ovarian tissue cryopreservation considered in females — specialist input required)

Paediatric HSCT — Long-term Follow-up Is Essential

Children who undergo HSCT for WAS require lifelong follow-up for late effects. Key areas:

Growth: Monitor height velocity; screen for GH deficiency (conditioning-related hypothalamic/pituitary damage)
Puberty: Tanner staging at each visit from age 8–10; sex hormones if pubertal delay
Fertility: Counselling about potential infertility; fertility preservation discussion before HSCT
Neurodevelopment: Some conditioning regimens (especially those involving TBI) can affect cognitive development
Secondary malignancy screening: Annual skin examination, age-appropriate cancer screening protocols
Vaccinations: Complete re-vaccination starting 6–12 months post-HSCT (killed vaccines first; live vaccines only after confirmed immune reconstitution)

Complication	Mechanism	Prevention/Management
Transfusion-associated iron overload	Each unit of packed red cells delivers ~200 mg iron; body has no active iron excretion mechanism	Monitor serum ferritin; iron chelation (deferasirox PO preferred in paediatrics) when ferritin > 1000 μg/L
Transfusion-associated GVHD (TA-GVHD)	Viable donor lymphocytes in transfused products engraft in immunocompromised recipient → attack host tissues	Irradiated blood products mandatory for all WAS patients ^[19]; fatality rate near 100% if it occurs
Alloimmunisation	Development of antibodies against donor HLA/platelet antigens → platelet refractoriness	Use HLA-matched or crossmatch-compatible platelets when refractoriness develops
Transfusion reactions (febrile non-haemolytic, allergic)	Recipient antibodies against donor leukocyte antigens or plasma proteins ^[26]	Leucodepleted products; pre-medication with paracetamol/antihistamine if recurrent reactions
Infection transmission	Blood-borne viruses (HBV, HCV, HIV — extremely rare with modern screening)	Donor screening; nucleic acid testing (NAT)

For patients receiving immunosuppressive agents for autoimmune complications (corticosteroids, rituximab, mycophenolate):

Complication	Drug	Mechanism
Further immunosuppression → infections	All immunosuppressants	Compounding the already impaired immunity of WAS
Cushing syndrome, growth retardation, osteoporosis	Corticosteroids	Chronic steroid use in children impairs linear growth (GH axis), causes centripetal obesity, skin thinning
Hypogammaglobulinaemia	Rituximab (anti-CD20)	B-cell depletion → worsened antibody deficiency; needs IVIG support
Progressive multifocal leukoencephalopathy (PML)	Rituximab (rare)	JC virus reactivation in immunocompromised state

Complication	Mechanism	Management
Secondary bacterial skin infection (impetiginisation)	Disrupted skin barrier → S. aureus colonisation → infection	Topical antiseptics (chlorhexidine wash, mupirocin); oral/IV antibiotics for extensive infection
Eczema herpeticum	HSV dissemination in eczematous skin due to broken barrier + T-cell deficiency	Medical emergency — IV aciclovir; can be fatal if untreated
Eczema vaccinatum	Dissemination of live vaccine virus (historically smallpox vaccine) in eczematous skin	Avoid all live vaccines; historical concern but relevant if inadvertent vaccination
Sleep disruption and quality of life	Severe pruritus → poor sleep → irritability, developmental impact	Sedating antihistamines (hydroxyzine) at night; comprehensive eczema management; psychological support
Skin-related bleeding	Eczema + thrombocytopenia → petechiae/purpura within eczematous areas ("bleeding into the eczema")	Eczema control + platelet support; highly characteristic of WAS

Complication	Mechanism	Approach
Failure to thrive	Chronic infections + bloody diarrhoea (iron/nutrient loss) + chronic inflammation (catabolic state) + poor oral intake (mucositis, oral candidiasis)	Dietitian input; caloric supplementation; NG/NJ tube feeding if needed; treat underlying infections
Developmental delay	Usually NOT intrinsic to WAS (unlike ataxia-telangiectasia); however, chronic illness, hospitalisations, and complications (especially ICH) can impair neurodevelopment	Regular developmental screening; early intervention referral if concerns; occupational/speech therapy
Psychological impact on child and family	Chronic illness burden, frequent hospitalisations, fear of bleeding, uncertainty about prognosis	Psychology/psychiatry referral; parent support groups; school liaison; sibling support

Organ System	Complications
Haematological	Microthrombocytopenia → bleeding (ICH, GI, mucosal); AIHA; autoimmune neutropenia; Evans syndrome; iron deficiency/overload
Immunological/Infectious	Recurrent sinopulmonary infections; PJP; eczema herpeticum; BCG-osis; sepsis; chronic diarrhoea; bronchiectasis
Autoimmune	AIHA, autoimmune thrombocytopenia, neutropenia, IgA nephropathy, vasculitis, IBD-like colitis, arthritis, cerebral vasculitis
Oncological	EBV-driven lymphoproliferative disease; NHL; leukaemia; MDS
Dermatological	Severe refractory eczema; secondary skin infections; eczema herpeticum
Gastrointestinal	Bloody diarrhoea; autoimmune enteropathy; chronic diarrhoea from infections (Cryptosporidium); malabsorption
Neurological	ICH; cerebral vasculitis; developmental sequelae of chronic illness
Treatment-related	HSCT complications (GVHD, VOD, infections, late effects); transfusion complications (iron overload, TA-GVHD); immunosuppression toxicity

High Yield Summary — Complications of WAS

Three causes of death (without HSCT): Infections (~50%), haemorrhage/ICH (~25%), malignancy (~25%)
Intracranial haemorrhage is the most feared acute complication — spontaneous when platelets < 10,000–20,000/μL; a leading cause of death in WAS.
Autoimmunity occurs in 40–72% of classic WAS patients — AIHA is most common; Evans syndrome is a particularly severe pattern. Development of autoimmunity elevates severity score to 5.
Malignancy risk is 13–22% lifetime — predominantly EBV-driven lymphoproliferative disease and B-cell lymphoma, especially with GI involvement ^[23].
WAS complications are progressive — T-cell numbers decline, autoimmunity and malignancy risk increase with age → HSCT should be performed early (ideally < 2 years) before complications accumulate.
Treatment-related complications (especially from HSCT) include GVHD, VOD, infections, endocrine dysfunction, infertility, and second malignancies — requiring lifelong follow-up.
Irradiated blood products are mandatory to prevent TA-GVHD ^[19].

Active Recall - Complications of WAS

^[2] Senior notes: Jerry's immunodeficiencies.pdf (p2 — WAS tetrad, low IgM, immunodeficiency not just infection but also autoimmune diseases and malignancy; treatment with HSCT) ^[13] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p50 — PLT low → WAS; Low IgM → WAS; combined immunodeficiencies including WAS) ^[19] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p22 — Irradiated blood products for immunocompromised; TA-GVHD prevention; oldest bag of blood in emergency) ^[20] Senior notes: Block A - Abnormal bleeding after tooth extraction_ bleeding tendency; thrombocytopenia.pdf (p8 — both platelet and coagulation problems can cause intracranial haemorrhages) ^[21] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p20 — OPSI, S. pneumoniae most common cause, pre/post-splenectomy vaccination and prophylaxis) ^[23] Lecture slides: Investigations of Imm Disorders 2025.pdf (p28 — X-linked PID: increased risk of infections, autoimmune especially neutropenia, lymphoproliferative/malignant complications especially lymphoma/GI involvement; IVIG replacement; Septrin prophylaxis) ^[24] Senior notes: Ryan Ho Haemtology.pdf (p156 — HSCT complications: early and late; cytopenia, mucositis, VOD, acute/chronic GVHD, infections, cardiovascular disease, endocrine dysfunction, second malignancy, cataracts) ^[25] Senior notes: Block A - Renal Replacement Therapies.pdf (p36 — long-term transplant complications: PTLD, EBV-related B-cell lymphoma; CMV, PJP, BK virus) ^[26] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p7 — acute transfusion reactions: febrile non-haemolytic, allergic, TACO, TRALI)

High Yield Summary

Wiskott-Aldrich Syndrome (WAS) — Key Points for Exams:

Definition: X-linked recessive PID caused by loss-of-function mutations in the WAS gene → absent/dysfunctional WASp → defective actin cytoskeleton in all haematopoietic cells.
Classification: IUIS Category 2 — Combined immunodeficiency with associated/syndromic features.
Classic tetrad: Eczema + Microthrombocytopenia (low count AND small size) + Immunodeficiency + Bloody diarrhoea.
Pathognomonic feature: Microthrombocytopenia — platelets are BOTH low in number AND small (low MPV < 5 fL). This is virtually unique to WAS.
Immunological profile: Low IgM, often elevated IgE and IgA, poor anti-polysaccharide antibody responses, progressive T-cell lymphopenia, impaired NK function.
Genotype-phenotype spectrum: Missense → XLT (mild); Null mutations → classic WAS (severe); Gain-of-function → XLN (neutropenia).
Complications: Autoimmunity (40–70%), malignancy (13–22%, especially lymphoma), ICH (leading cause of death).
Definitive treatment: Haematopoietic stem cell transplantation (HSCT) — curative. Gene therapy is emerging.
Key differential: Any male infant with severe eczema → check CBC + MPV. Small platelets distinguish WAS from ITP (where platelets are large).
Inheritance: X-linked recessive → affects males; carrier testing and genetic counselling for maternal relatives essential.

High Yield Summary – Differential Diagnosis of WAS

The WAS tetrad (eczema + microthrombocytopenia + immunodeficiency + bloody diarrhoea) is fairly unique; no other single condition perfectly replicates all four.
The MPV is the critical discriminating test: Small platelets (MPV < 5 fL) in a thrombocytopenic male infant = WAS until proven otherwise.
Most common DDx pitfalls in exams:
- Confusing WAS with ITP → ITP has LARGE platelets, no eczema, no immunodeficiency, previously well child
- Confusing WAS with atopic dermatitis → always check CBC in male infants with severe refractory eczema
- Confusing WAS with Bernard-Soulier → BSS has LARGE/giant platelets, no eczema, no immunodeficiency
Other PIDs with eczema: HIES (very high IgE, cold abscesses, pneumatoceles), SCID/Omenn (erythroderma, severe lymphopenia), IPEX (neonatal diabetes, enteropathy), DiGeorge (cardiac, hypoCa)
WAS is classified under IUIS Table 2 — combined immunodeficiency with associated or syndromic features ^[12]

High Yield Summary — Diagnosis of WAS

The MPV is the most discriminating screening test: PLT low + MPV < 5 fL in a male infant = WAS until proven otherwise ^[13].
Immunoglobulin pattern: Low IgM is characteristic and flagged on GC lecture slides ^[13]. IgE often elevated. IgG normal or low.
WASp expression by flow cytometry is the fastest confirmatory test — absent WASp = classic WAS.
Genetic testing is required in all cases ^[14] — it confirms diagnosis, predicts severity, enables carrier testing and prenatal diagnosis.
Approach to PID diagnosis: Clinical history → Physical examination → Phenotypic investigations (IgG, IgA, IgM levels; Vaccine responses; T, B, NK cell enumerations; Lymphocyte subsets; Cell function) → Genetic testing ^[14].
Always rule out pseudothrombocytopenia (EDTA artefact) before pursuing further workup — check PBS for platelet clumps ^[15].
Paediatric normal values differ from adults: ALC < 3000/μL in infants < 1 year or < 1000/μL in children > 1 year is abnormal ^[13].

High Yield Summary — Management of WAS

HSCT is the only curative treatment for WAS — indicated for clinical severity score ≥ 3. Listed on GC 060 lecture slide as an established indication for allogeneic HSCT ^[17].
Donor preference: Matched sibling donor > Matched unrelated donor > Haploidentical/Cord blood.
HSCT procedure: Conditioning (high-dose chemo/radio to eradicate diseased marrow) → Donor graft (replace with healthy HSCs) → Immunosuppression (prevent GVHD) ^[16].
Supportive care for ALL patients: Avoid live vaccines; IVIG replacement; antimicrobial prophylaxis (co-trimoxazole for PJP); eczema management; platelet transfusion for acute bleeding (irradiated products); avoidance of NSAIDs/aspirin.
Splenectomy is generally avoided in WAS — improves platelet count but dramatically worsens infection risk in a child who already has poor antibody responses.
Gene therapy is emerging as a curative option, especially for patients lacking suitable HSCT donors.
Irradiated blood products are mandatory for all WAS patients to prevent TA-GVHD ^[19].
Transplant early — outcomes are better when HSCT is performed at younger age (< 5 years, ideally < 2 years) before complications accumulate.

High Yield Summary — Complications of WAS

Three causes of death (without HSCT): Infections (~50%), haemorrhage/ICH (~25%), malignancy (~25%)
Intracranial haemorrhage is the most feared acute complication — spontaneous when platelets < 10,000–20,000/μL; a leading cause of death in WAS.
Autoimmunity occurs in 40–72% of classic WAS patients — AIHA is most common; Evans syndrome is a particularly severe pattern. Development of autoimmunity elevates severity score to 5.
Malignancy risk is 13–22% lifetime — predominantly EBV-driven lymphoproliferative disease and B-cell lymphoma, especially with GI involvement ^[23].
WAS complications are progressive — T-cell numbers decline, autoimmunity and malignancy risk increase with age → HSCT should be performed early (ideally < 2 years) before complications accumulate.
Treatment-related complications (especially from HSCT) include GVHD, VOD, infections, endocrine dysfunction, infertility, and second malignancies — requiring lifelong follow-up.
Irradiated blood products are mandatory to prevent TA-GVHD ^[19].

Wiskott-aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS) — Paediatric Primary Immunodeficiency

2. Epidemiology

3. Anatomy and Function: The WASp Protein and Actin Cytoskeleton

4. Aetiology

5. Pathophysiology — Connecting the Gene Defect to Clinical Features

6. Classification

7. Clinical Features

8. Family-Centred Care and Communication Considerations (Paediatric)

Active Recall - Wiskott-Aldrich Syndrome

A. Differential Diagnosis by Presenting Feature

A1. Male Infant with Thrombocytopenia ± Bleeding

Active Recall - DDx of Wiskott-Aldrich Syndrome

1. Diagnostic Criteria

3. Investigation Modalities — Detailed Guide

3.1 First-Line Screening Investigations

3.2 Second-Line Immunological Investigations

3.3 Confirmatory Investigations — WASp-Specific

3.4 Additional Supportive and Monitoring Investigations

Active Recall - Diagnosis and Investigations of WAS

2. Immediate Measures at Diagnosis (All Patients)

3. Supportive Care (All Patients, Ongoing)

3.1 Management of Thrombocytopenia and Bleeding

4. Definitive Curative Treatment

4.1 Haematopoietic Stem Cell Transplantation (HSCT)

6. Special Paediatric Considerations

Active Recall - Management of WAS

1. Haemorrhagic Complications

2. Infectious Complications

3. Autoimmune Complications

4. Malignant Complications

5. Complications of Treatment

Active Recall - Complications of WAS

On this page

Wiskott-aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS) — Paediatric Primary Immunodeficiency

1. Definition

2. Epidemiology

Incidence and Prevalence

Demographics

Hong Kong Context

Risk Factors

3. Anatomy and Function: The WASp Protein and Actin Cytoskeleton

The WAS Gene

WASp Structure and Function

Why Actin Cytoskeleton Matters in Immunity

4. Aetiology

Genetic Basis

Genotype-Phenotype Correlation

Hong Kong / Chinese Population Genetics

5. Pathophysiology — Connecting the Gene Defect to Clinical Features

5.1 Microthrombocytopenia

5.2 Immunodeficiency (Combined T-cell and B-cell Dysfunction)

5.3 Eczema

5.4 Autoimmunity

5.5 Malignancy

6. Classification

6.1 Within the IUIS Classification of Inborn Errors of Immunity (2022)

6.2 The WAS Phenotypic Spectrum

6.3 Clinical Scoring System (Ochs/Zhu Score)

7. Clinical Features

Age of Presentation

7.1 Symptoms (with Pathophysiological Basis)

7.2 Signs (with Pathophysiological Basis)

7.3 Immunological Profile

7.4 Natural History (Without Treatment)

8. Family-Centred Care and Communication Considerations (Paediatric)

Communication with Family

Age-Appropriate Considerations

Infection Prevention Education

9. Comparison with Other PIDs with Associated/Syndromic Features

Active Recall - Wiskott-Aldrich Syndrome

References

Differential Diagnosis of Wiskott-Aldrich Syndrome (WAS) — Paediatric Approach

Framing the Differential Diagnosis

A. Differential Diagnosis by Presenting Feature

A1. Male Infant with Thrombocytopenia ± Bleeding

Congenital / Inherited Thrombocytopenia

Acquired Thrombocytopenia (Paediatric)

A2. Infant/Child with Eczema — When to Suspect WAS Rather Than Atopic Dermatitis

A3. Infant/Child with Recurrent Infections — WAS vs Other Primary Immunodeficiencies

B. Diagnostic Differentiation Algorithm

C. Summary Comparison Table — The "Eczema + Thrombocytopenia" Pair

D. Approach to the DDx in Clinical Practice — Thinking Framework

Active Recall - DDx of Wiskott-Aldrich Syndrome

References

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Wiskott-Aldrich Syndrome (WAS) — Paediatric Approach

1. Diagnostic Criteria

1.1 Clinical Diagnostic Suspicion — "When Should I Think of WAS?"

1.2 Proposed Diagnostic Framework (Synthesis of International Expert Consensus)

1.3 Clinical Severity Scoring (Ochs/Zhu)

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Guide

3.1 First-Line Screening Investigations

3.1.1 Complete Blood Count (CBC) with MPV and Differential

3.1.2 Peripheral Blood Smear (PBS)

3.1.3 Coagulation Profile (PT, APTT, Fibrinogen)

3.2 Second-Line Immunological Investigations

3.2.1 Serum Immunoglobulin Levels (IgG, IgA, IgM, IgE)

3.2.2 Isohemagglutinins (Anti-A, Anti-B)

3.2.3 Vaccine Antibody Responses (Functional Antibody Assessment)

3.2.4 Lymphocyte Subset Enumeration (T, B, NK Cells by Flow Cytometry)

3.2.5 Lymphocyte Proliferation Assays (T-Cell Function)

3.3 Confirmatory Investigations — WASp-Specific

3.3.1 WASp Expression by Flow Cytometry

3.3.2 WAS Gene Sequencing (Definitive Diagnosis)

3.4 Additional Supportive and Monitoring Investigations

3.4.1 Autoimmune Workup

3.4.2 Infection Screening

3.4.3 Imaging

3.4.4 HLA Typing

3.4.5 Bone Marrow Examination

4. Summary — Investigation Pathway

Active Recall - Diagnosis and Investigations of WAS