Definition/General
Introduction:
Griscelli syndrome (GS) is a rare autosomal recessive disorder characterized by partial oculocutaneous albinism and variable immunodeficiency
Three types are recognized based on different gene mutations: MYO5A (Type 1), RAB27A (Type 2), and MLPH (Type 3)
Type 2 is associated with severe immunodeficiency.
Origin:
Results from mutations affecting melanosome transport and immune cell function
Type 1: MYO5A mutations (neurological symptoms)
Type 2: RAB27A mutations (immunodeficiency and HLH)
Type 3: MLPH mutations (isolated albinism)
The defects affect vesicle trafficking in different cell types.
Classification:
Classified into three types: Type 1 (GS1): MYO5A mutations, neurological defects
Type 2 (GS2): RAB27A mutations, immunodeficiency, HLH
Type 3 (GS3): MLPH mutations, isolated albinism
Type 2 most severe with immune dysfunction.
Epidemiology:
Very rare disorder with less than 150 cases reported worldwide
Type 2 most common among severe forms
Equal gender distribution
Consanguinity common
Higher prevalence in certain populations (Turkish, Mediterranean).
Clinical Features
Presentation:
Silvery-gray hair (pathognomonic)
Partial oculocutaneous albinism
Recurrent infections (Type 2)
Hemophagocytic lymphohistiocytosis (Type 2)
Neurological defects (Type 1)
Accelerated phase in Type 2.
Symptoms:
Distinctive silvery hair from birth
Hypopigmentation of skin and eyes
Photophobia and vision problems
Recurrent fever (Type 2)
Hepatosplenomegaly (Type 2)
Seizures and developmental delay (Type 1).
Risk Factors:
Consanguineous parents
Family history of albinism
Mediterranean or Turkish ancestry
Sibling with GS
Carrier parents
No environmental risk factors.
Screening:
Hair microscopy (melanin clumping)
Complete blood count
Immune function tests
Bone marrow examination
Genetic testing
NK cell function (Type 2)
Electron microscopy.
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Gross Description
Appearance:
Bone marrow aspirate shows normal cellularity in Types 1 and 3
Type 2 may show hemophagocytosis
Normal cell morphology
No specific granule abnormalities
Reactive changes in Type 2.
Characteristics:
Normal bone marrow architecture
Hemophagocytic changes in Type 2 during accelerated phase
Increased histiocytes may be present
Normal hematopoietic cells
No specific morphological abnormalities.
Size Location:
Lymph nodes enlarged (Type 2)
Hepatosplenomegaly common in Type 2
Normal bone marrow distribution
Skin hypopigmentation
CNS involvement (Type 1).
Multifocality:
Systemic hypopigmentation
Multi-organ involvement in Type 2
Accelerated phase development
CNS predominant in Type 1
Isolated skin involvement in Type 3.
Microscopic Description
Histological Features:
Normal bone marrow morphology in stable phase
Hemophagocytosis in Type 2 accelerated phase
Increased activated macrophages
Normal granulopoiesis
No specific cytoplasmic inclusions.
Cellular Characteristics:
Morphologically normal hematopoietic cells
Hemophagocytic macrophages in Type 2
Normal nuclear morphology
No giant granules (unlike Chediak-Higashi)
Activated immune cells in Type 2.
Architectural Patterns:
Preserved bone marrow architecture
Increased histiocytic infiltration in Type 2
Normal sinusoidal pattern
No fibrosis
Reactive lymphoid aggregates possible.
Grading Criteria:
Type classification by genetic testing
Hair microscopy findings
Immune function assessment
HLH criteria in Type 2
Neurological involvement in Type 1
NK cell function severely impaired in Type 2.
Immunohistochemistry
Positive Markers:
CD68 highlights increased macrophages
CD163 marks activated macrophages
S-100 in melanocytes (reduced)
MPO shows normal granulopoiesis
CD3/CD20 show lymphoid cells.
Negative Markers:
Giant granule markers negative
Viral markers variable
Melanin reduced in melanocytes
Some lysosomal markers may be abnormal.
Diagnostic Utility:
Demonstrates hemophagocytic activity (Type 2)
Shows normal cell morphology
Confirms absence of giant granules
Assesses immune cell populations
Identifies activated macrophages
Distinguishes from Chediak-Higashi.
Molecular Subtypes:
Type 1 (GS1): MYO5A mutations
Type 2 (GS2): RAB27A mutations
Type 3 (GS3): MLPH mutations
Different clinical phenotypes
Variable prognosis.
Molecular/Genetic
Genetic Mutations:
MYO5A mutations (Type 1, chromosome 15q21)
RAB27A mutations (Type 2, chromosome 15q21)
MLPH mutations (Type 3, chromosome 2q37)
Autosomal recessive inheritance
Different mutation spectra in different populations.
Molecular Markers:
Defective vesicle trafficking
Abnormal melanosome transport
Impaired cytotoxic granule exocytosis (Type 2)
Reduced NK cell function (Type 2)
Normal lysosomal enzymes.
Prognostic Significance:
Type 1: neurological deterioration
Type 2: poor prognosis without BMT
Type 3: cosmetic issues only
Accelerated phase often fatal in Type 2
Early BMT improves outcomes
Gene therapy experimental.
Therapeutic Targets:
Bone marrow transplantation (Type 2, curative)
HLH treatment protocols
Immunosuppressive therapy
Supportive care (Type 1)
Cosmetic management (Type 3)
Gene therapy (investigational).
Differential Diagnosis
Similar Entities:
Chediak-Higashi syndrome
Hermansky-Pudlak syndrome
Oculocutaneous albinism
Hemophagocytic lymphohistiocytosis
Other albinism syndromes
Primary immunodeficiencies.
Distinguishing Features:
GS: Silvery-gray hair
GS: Hair microscopy characteristic
GS: No giant granules
CHS: Giant azurophilic granules
CHS: Recurrent infections
HPS: Platelet storage pool defect
HPS: Pulmonary fibrosis
OCA: No immunodeficiency.
Diagnostic Challenges:
Distinguishing GS types
Confirming genetic diagnosis
Recognizing accelerated phase
Hair microscopy interpretation
NK cell function testing
Family screening.
Rare Variants:
Atypical presentations
Mild Type 2
Late-onset symptoms
Compound heterozygous mutations
Phenotypic variability.
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
Griscelli Syndrome
Classification
Classification: [Type 1/2/3] Griscelli syndrome
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), [with/without] hemophagocytosis
Lineage Assessment
All lineages morphologically normal. Hemophagocytosis: [present/absent]
Morphological Features
Shows normal hematopoietic cells [with hemophagocytic changes if Type 2]
Special Studies
Hair microscopy: recommend for diagnosis
Genetic testing: recommend GS gene panel
NK cell function: [if Type 2 suspected]
Clinical Correlation
Findings consistent with Griscelli syndrome. Recommend genetic counseling
Final Diagnosis
Bone marrow [normal/showing hemophagocytosis] consistent with Griscelli syndrome