Makindo Medical Notes

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