Definition/General
Introduction:
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, and giant cytoplasmic granules in leukocytes
It results from mutations in the LYST gene affecting lysosomal trafficking
The syndrome predisposes to hemophagocytic lymphohistiocytosis.
Origin:
Results from mutations in LYST gene (lysosomal trafficking regulator) on chromosome 1q42.3
The defect causes abnormal fusion of lysosomes and secretory granules
Leads to formation of giant cytoplasmic granules
Affects multiple cell types including neutrophils, lymphocytes, and melanocytes.
Classification:
Classified into two phases: Stable phase (chronic infections, bleeding tendency)
Accelerated phase (hemophagocytic syndrome, fever, hepatosplenomegaly)
Classical CHS (early onset)
Atypical CHS (milder, later onset)
Adult form (rare).
Epidemiology:
Very rare disorder with less than 500 cases reported worldwide
Equal gender distribution
Autosomal recessive inheritance
Consanguinity common
Higher prevalence in certain populations
Poor prognosis without treatment.
Clinical Features
Presentation:
Oculocutaneous albinism (partial)
Recurrent bacterial infections
Bleeding tendency (platelet dysfunction)
Progressive neurodegeneration
Giant granules in leukocytes
Accelerated phase (HLH-like syndrome).
Symptoms:
Silvery hair and light skin
Photophobia and nystagmus
Recurrent pyogenic infections
Easy bruising and bleeding
Peripheral neuropathy
Intellectual disability
Fever and hepatosplenomegaly (accelerated phase).
Risk Factors:
Consanguineous parents
Family history of albinism or infections
Sibling with CHS
Carrier parents
Certain ethnic populations
No environmental risk factors.
Screening:
Complete blood count with microscopic examination
Giant granules in neutrophils (pathognomonic)
Bone marrow examination
Genetic testing for LYST mutations
NK cell function tests
Electron microscopy.
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Gross Description
Appearance:
Bone marrow aspirate shows normal cellularity
Giant azurophilic granules in neutrophils and eosinophils
Abnormal granules in other cells
Normal cell counts typically
May show hemophagocytosis in accelerated phase.
Characteristics:
Pathognomonic giant granules in granulocytes
Normal bone marrow architecture
Hemophagocytic changes may be present
Increased storage histiocytes
Normal megakaryocytes with possible giant granules.
Size Location:
Diffuse granule abnormalities
All granulocytes affected
Lymph nodes enlarged (reactive)
Hepatosplenomegaly common
Bone marrow distribution normal.
Multifocality:
Systemic granule abnormalities
Multi-organ involvement
Progressive disease
Accelerated phase development
Widespread hemophagocytosis.
Microscopic Description
Histological Features:
Giant azurophilic granules in neutrophils (pathognomonic)
Abnormal granules in eosinophils and basophils
Large granules in lymphocytes and monocytes
Normal cell morphology otherwise
Hemophagocytosis in accelerated phase.
Cellular Characteristics:
Giant peroxidase-positive granules in neutrophils
Fused lysosomal structures
Normal nuclear morphology
Abnormal degranulation
Reduced bactericidal activity
Platelet giant granules (dense bodies).
Architectural Patterns:
Preserved bone marrow architecture
Normal cellular distribution
Possible histiocytic infiltration
Hemophagocytic changes in accelerated phase
No fibrosis typically.
Grading Criteria:
Diagnosis by giant granule presence
Granule size >2-3 times normal
Present in >5% of neutrophils
Accelerated phase criteria (fever, splenomegaly, cytopenias, hemophagocytosis)
NK cell function severely reduced.
Immunohistochemistry
Positive Markers:
MPO highlights giant granules in neutrophils
Elastase positive in abnormal granules
CD68 marks histiocytes/macrophages
Lysozyme in giant granules
Perforin in NK cells (may be abnormal).
Negative Markers:
Normal bacterial markers (poor killing)
Some lysosomal enzymes may be redistributed
Melanin reduced in melanocytes
Normal lymphoid markers present.
Diagnostic Utility:
Confirms giant granule nature
Demonstrates lysosomal enzyme presence
Shows abnormal degranulation
Identifies hemophagocytic cells
Assesses NK cell function
Pathognomonic finding.
Molecular Subtypes:
Classical CHS (severe LYST mutations)
Atypical CHS (milder mutations)
Adult-onset CHS
Different mutation types
Genotype-phenotype correlations.
Molecular/Genetic
Genetic Mutations:
LYST gene mutations (chromosome 1q42.3)
Frameshift mutations (severe phenotype)
Nonsense mutations (classical CHS)
Missense mutations (milder phenotype)
Large deletions
Compound heterozygous mutations.
Molecular Markers:
Defective lysosomal trafficking
Abnormal granule fusion
Impaired degranulation
Reduced NK cell cytotoxicity
Abnormal melanosome transport
Defective bactericidal activity.
Prognostic Significance:
Severe mutations early acceleration
Classical form poor prognosis
Accelerated phase often fatal
Bone marrow transplant curative
Early treatment improves outcomes
Atypical forms better prognosis.
Therapeutic Targets:
Bone marrow transplantation (curative)
Antimicrobial prophylaxis
Ascorbic acid (improper granule function)
HLH treatment for accelerated phase
Supportive care
Gene therapy (experimental).
Differential Diagnosis
Similar Entities:
Griscelli syndrome (similar albinism)
Hermansky-Pudlak syndrome
May-Hegglin anomaly
Alder-Reilly anomaly
Pseudo-Chediak-Higashi (drug-induced)
Other storage disorders.
Distinguishing Features:
CHS: Giant azurophilic granules
CHS: Recurrent infections
CHS: LYST mutations
Griscelli: Different hair microscopy
Griscelli: RAB27A mutations
HPS: Platelet storage pool defect
May-Hegglin: Döhle-like bodies
May-Hegglin: MYH9 mutations.
Diagnostic Challenges:
Confirming genetic diagnosis
Distinguishing from other albinism syndromes
Recognizing accelerated phase
NK cell function testing
Family screening
Treatment timing.
Rare Variants:
Atypical CHS (milder phenotype)
Adult-onset CHS
CHS without albinism (rare)
Pseudo-CHS (acquired)
Partial phenotypes.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Chediak-Higashi Syndrome
Classification
Classification: Lysosomal storage disorder with immunodeficiency
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with characteristic giant granules
Lineage Assessment
Granulopoiesis: giant azurophilic granules in neutrophils. Erythropoiesis: normal. Megakaryopoiesis: normal
Morphological Features
Shows pathognomonic giant azurophilic granules in neutrophils and other granulocytes
Special Studies
Giant granules: present in neutrophils (pathognomonic)
Genetic testing: recommend LYST gene analysis
NK cell function: recommend testing
Clinical Correlation
Findings diagnostic of Chediak-Higashi syndrome. Recommend genetic counseling
Final Diagnosis
Bone marrow showing Chediak-Higashi syndrome with characteristic giant granules