Chediak-Higashi syndrome
Summary
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the LYST gene, leading to defective lysosomal trafficking and giant granules in cells. Clinically, it presents with recurrent pyogenic infections, partial albinism, peripheral neuropathy, and a bleeding tendency. Patients are at risk for developing an 'accelerated phase' resembling hemophagocytic lymphohistiocytosis (HLH).
Detail
CHS results from mutations in the LYST (lysosomal trafficking regulator) gene, which impairs proper fusion and trafficking of lysosomes and lysosome-related organelles (e.g., melanosomes, platelet dense granules, cytotoxic granules of NK cells and CTLs). This defect causes giant, dysfunctional granules visible on peripheral blood smear within neutrophils and other leukocytes—a classic diagnostic finding.
Key clinical features: - Recurrent pyogenic infections (especially with Staphylococcus aureus and Streptococcus species) due to impaired neutrophil chemotaxis and degranulation. - Partial oculocutaneous albinism (silvery hair, light skin, photophobia) from defective melanosome transport. - Peripheral and cranial neuropathy, developmental delay, and other neurologic manifestations due to lysosomal dysfunction in neurons. - Mild bleeding diathesis due to abnormal platelet dense granules. - Progressive, life-threatening 'accelerated phase': lymphohistiocytic infiltration of organs, resembling HLH, triggered often by viral infections (e.g., EBV), with fever, hepatosplenomegaly, pancytopenia, and hemophagocytosis.
Pathophysiology ties together defects in the LYST protein affecting all lysosome-related organelles—giant granules in neutrophils/lymphocytes, abnormal melanosomes in melanocytes, and defective platelet dense granules.
Diagnosis: peripheral smear showing giant cytoplasmic granules in leukocytes, confirmed by genetic testing.
Management: Hematopoietic stem cell transplantation (HSCT) is the definitive treatment, ideally before the accelerated phase develops, as it corrects the immunologic defects (though neurologic and pigmentary abnormalities may persist). Supportive care includes prophylactic antibiotics and monitoring for HLH-like accelerated phase.
High-yield associations: giant granules, partial albinism, recurrent infections, neuropathy, accelerated phase (HLH-like), LYST gene, autosomal recessive.
Sources
- First Aid for the USMLE Step 1
- Robbins and Cotran Pathologic Basis of Disease
- UpToDate: Chediak-Higashi syndrome
- Kumar, Abbas, Aster - Robbins Basic Pathology
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