Related Subjects:
|X linked Agammaglobulinaemia (Bruton)
|X-linked lymphoproliferative disease (Children)
|Chediak Higashi syndrome
|Common variable immunodeficiency
|Severe combined immunodeficiency disorders
|DiGeorge syndrome (thymic aplasia)
|Selective IgA deficiency
|Wiskott-Aldrich syndrome (Children)
|T lymphocytes
🧑⚕️ Mentor’s note: Chediak–Higashi is a classic “granule trafficking” disorder-think faulty delivery of the immune system’s toxic payload. That single idea explains the triad (albinism, infections, bleeding) and the dangerous HLH “accelerated phase.” Keep LYST and giant granules front-of-mind for exams.
📖 About
- Chediak–Higashi Syndrome (CHS) is a rare, autosomal recessive immunodeficiency due to defective lysosomal trafficking.
- Leads to recurrent infections, partial albinism, bleeding diathesis, neuropathy, and lymphoproliferative complications.
- Characteristic triad: partial albinism + recurrent pyogenic infections + giant granules in leukocytes.
🧬 Aetiology & Pathophysiology
- Loss-of-function mutations in LYST (CHS1) impair regulation of lysosome size and movement.
- Microtubule- and actin-dependent trafficking failure → abnormally large, dysfunctional granules in neutrophils, NK/CTLs, platelets, and melanocytes.
- Defective chemotaxis, phagolysosome fusion, degranulation, and intracellular killing.
- ↓ NK/CTL cytotoxicity predisposes to an HLH-like accelerated phase (often EBV-triggered).
- Typical pathogens: recurrent pyogenic infections with Staphylococcus and Streptococcus.
🩺 Clinical Features
- Partial oculocutaneous albinism: silvery hair, light skin/eyes, pigment dilution; photophobia and nystagmus.
- Recurrent skin and respiratory infections, periodontal disease, poor wound healing.
- Bleeding tendency from platelet dense-granule defect → bruising, epistaxis, menorrhagia.
- Accelerated phase (HLH-like): fever, hepatosplenomegaly, cytopenias, organ infiltration; can be rapidly fatal.
- Progressive peripheral neuropathy and neurodegeneration in survivors without early HSCT.
🔬 Investigations
- Blood film: pathognomonic giant azurophilic granules in neutrophils/lymphocytes/platelets.
- FBC: neutropenia ± pancytopenia; inflammatory markers during infections/HLH.
- Platelet function: dense-body deficiency → mild coagulation abnormalities (BT/aggregation).
- NK/CTL degranulation assays (e.g., CD107a) show impaired cytotoxicity.
- HLH work-up if unwell: ferritin, triglycerides, fibrinogen, sCD25, bone marrow as indicated.
- Genetics: confirm LYST mutation; hair-shaft microscopy may show uneven melanin distribution.
⚕️ Management
- Curative: early allogeneic HSCT (best before/after stabilising accelerated phase). HSCT corrects immune/haematologic defects but not pigmentary or established neurological changes.
- Supportive: prompt treatment and prophylaxis for infections (consider anti-staphylococcal cover), meticulous dental care, blood products if bleeding; avoid live vaccines unless immunology advises otherwise.
- Neutropenia: G-CSF may help selected patients; consider IVIG if recurrent/severe infections per specialist advice.
- Accelerated phase (HLH): manage per HLH protocols (e.g., dexamethasone ± etoposide/ciclosporin) and treat triggers (e.g., EBV), then proceed to urgent HSCT in a specialist centre.
- UK context: coordinate early with regional paediatric immunology/HSCT services; genetic counselling for families.
📉 Prognosis
- Without HSCT, many children die in the first decade from infections
