Definition/General
Introduction:
Hermansky-Pudlak syndrome (HPS) is a group of autosomal recessive disorders characterized by oculocutaneous albinism, platelet storage pool deficiency, and lysosomal ceroid accumulation
Multiple subtypes exist based on different gene mutations affecting lysosome-related organelle biogenesis
Some subtypes develop pulmonary fibrosis.
Origin:
Results from mutations in genes encoding BLOC complexes (biogenesis of lysosome-related organelles complex)
Ten subtypes (HPS1-10) identified
The defects affect melanosome, platelet dense granule, and lysosome biogenesis
Leads to abnormal organelle formation in multiple cell types.
Classification:
Classified into ten subtypes: HPS-1 (most common, HPS1 gene)
HPS-2 (AP3B1 gene)
HPS-3 (HPS3 gene)
HPS-4 (HPS4 gene)
HPS-5 through HPS-10 (various genes)
Pulmonary fibrosis in HPS-1, 2, and 4.
Epidemiology:
Rare disorder with variable prevalence by population
High prevalence in Puerto Rico (HPS-1 and 3)
Equal gender distribution
Consanguinity increases risk
Different subtypes in different populations.
Clinical Features
Presentation:
Oculocutaneous albinism (variable severity)
Bleeding tendency (platelet dysfunction)
Nystagmus and photophobia
Pulmonary fibrosis (HPS-1, 2, 4)
Granulomatous colitis (HPS-1, 4)
Immunodeficiency (HPS-2).
Symptoms:
Light skin and hair pigmentation
Vision problems (nystagmus, reduced acuity)
Easy bruising and bleeding
Progressive dyspnea (pulmonary fibrosis)
Chronic diarrhea (colitis)
Recurrent infections (HPS-2).
Risk Factors:
Consanguineous parents
Puerto Rican ancestry (HPS-1, 3)
Swiss ancestry (HPS-3)
Family history of albinism or bleeding
Carrier parents
No environmental risk factors.
Screening:
Complete blood count with platelet function studies
Platelet aggregometry
Electron microscopy (absent dense granules)
Genetic testing
Pulmonary function tests
Ophthalmological examination.
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Gross Description
Appearance:
Bone marrow aspirate shows normal cellularity and morphology
Normal platelet numbers
Megakaryocytes appear normal
No specific morphological abnormalities
Possible storage material in some cells.
Characteristics:
Normal bone marrow architecture
Morphologically normal hematopoietic cells
Functional platelet defect not morphologically evident
Possible ceroid accumulation
No granule abnormalities visible by light microscopy.
Size Location:
Normal bone marrow distribution
Systemic hypopigmentation
Pulmonary involvement (certain subtypes)
Gastrointestinal involvement
No focal bone marrow lesions.
Multifocality:
Systemic organelle dysfunction
Multi-organ involvement
Progressive complications
Subtype-specific manifestations
Lysosomal storage in various tissues.
Microscopic Description
Histological Features:
Normal bone marrow morphology by light microscopy
Normal megakaryocyte morphology
Possible storage material in macrophages
Normal other lineages
Electron microscopy shows absent platelet dense granules.
Cellular Characteristics:
Morphologically normal cells by light microscopy
Absent platelet dense granules (EM finding)
Abnormal melanosome structure
Lysosomal storage material
Normal nuclear morphology.
Architectural Patterns:
Preserved bone marrow architecture
Normal cellular distribution
No inflammatory infiltrates
No fibrosis
Storage material may be present in histiocytes.
Grading Criteria:
Diagnosis by clinical triad: albinism, bleeding tendency, storage pool deficiency
Absent platelet dense granules (EM)
Genetic testing confirms subtype
Platelet aggregation abnormalities
Pulmonary involvement in specific subtypes.
Immunohistochemistry
Positive Markers:
CD61 and CD41 highlight normal platelets
CD68 marks macrophages (may contain storage material)
MPO shows normal granulopoiesis
Glycophorin A shows normal erythropoiesis
Tyrosinase in melanocytes.
Negative Markers:
Dense granule markers absent in platelets
Some lysosomal markers may be redistributed
Melanin reduced in melanocytes
Giant granule markers negative.
Diagnostic Utility:
Demonstrates normal platelet morphology
Shows storage material in macrophages
Confirms absence of giant granules
Assesses melanocyte function
Requires electron microscopy for diagnosis
Functional studies essential.
Molecular Subtypes:
HPS-1 (HPS1 gene, most common)
HPS-2 (AP3B1 gene, immunodeficiency)
HPS-3 (HPS3 gene, mild)
HPS-4 (HPS4 gene, pulmonary fibrosis)
HPS-5 through HPS-10 (various genes).
Molecular/Genetic
Genetic Mutations:
HPS1 mutations (most common subtype)
AP3B1 mutations (HPS-2, immunodeficiency)
HPS3 mutations (mild phenotype)
HPS4 mutations (pulmonary fibrosis)
Multiple other genes (HPS5-10)
Different founder mutations in different populations.
Molecular Markers:
Defective BLOC complex function
Abnormal organelle biogenesis
Absent platelet dense granules
Ceroid accumulation
Abnormal melanosome structure
Lysosomal dysfunction.
Prognostic Significance:
HPS-1, 2, 4 develop pulmonary fibrosis
HPS-2 has immunodeficiency
HPS-3 mildest phenotype
Pulmonary fibrosis major cause of mortality
No curative treatment
Supportive care essential.
Therapeutic Targets:
Antifibrotic agents (pirfenidone, nintedanib)
Lung transplantation (end-stage fibrosis)
Platelet transfusions (severe bleeding)
Sunscreen and protection
Supportive care
Gene therapy (experimental).
Differential Diagnosis
Similar Entities:
Chediak-Higashi syndrome
Griscelli syndrome
Other oculocutaneous albinism
Wiskott-Aldrich syndrome
Bernard-Soulier syndrome
Gray platelet syndrome.
Distinguishing Features:
HPS: Platelet storage pool defect
HPS: Absent dense granules (EM)
HPS: Pulmonary fibrosis (some types)
CHS: Giant granules
CHS: Recurrent infections
WAS: Small platelets
WAS: Immunodeficiency
BSS: Giant platelets.
Diagnostic Challenges:
Confirming storage pool deficiency
Identifying HPS subtype
Electron microscopy requirements
Genetic testing complexity
Pulmonary monitoring
Family screening.
Rare Variants:
Atypical HPS presentations
Mild phenotypes
Adult-onset symptoms
Isolated bleeding tendency
Compound heterozygous mutations.
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
Hermansky-Pudlak Syndrome (Suspected)
Classification
Classification: Lysosomal storage disorder with albinism and platelet dysfunction
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with morphologically normal cells
Lineage Assessment
All lineages morphologically normal. Megakaryopoiesis: adequate with normal morphology
Morphological Features
Shows normal bone marrow morphology. Storage material may be present in macrophages
Special Studies
Electron microscopy: recommend for platelet dense granule assessment
Platelet function: recommend aggregometry studies
Genetic testing: recommend HPS gene panel
Clinical Correlation
Normal bone marrow morphology. Clinical suspicion of HPS requires specialized testing
Final Diagnosis
Bone marrow morphology normal. Clinical features suggest Hermansky-Pudlak syndrome - requires confirmation