Hermansky-Pudlak Syndrome Overview
Definition and Genetics
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder caused by mutations in at least 10 genes (HPS1-9, plus AP3B1, AP3D1, BLOC1S3, BLOC1S6, DTNBP1) that disrupt lysosome-related organelle formation, resulting in oculocutaneous albinism and bleeding diathesis present from birth, with life-threatening pulmonary fibrosis emerging in the third decade in specific subtypes. 1, 2, 3
- The condition affects approximately 1 in 500,000 to 1,000 individuals worldwide, though prevalence reaches 1 in 1,800 in Puerto Rican populations and is also elevated in Ashkenazi Jewish populations 1, 3, 4
- HPS genes encode components of four protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 through -3 (BLOC-1, BLOC-2, BLOC-3) 2, 4
Clinical Manifestations
Universal Features (All HPS Types)
- Oculocutaneous albinism: Pigmentary dilution affecting skin, hair, and eyes, present from birth 5, 1, 6
- Bleeding diathesis: Severe thrombocytopenia and/or thrombasthenia due to absent platelet dense granules, causing easy bruising and prolonged bleeding 5, 2, 6
- Ceroid accumulation: Deposition of ceroid-like material in reticuloendothelial cells throughout the body 6, 4
Subtype-Specific Complications
HPS Type 1,2, and 4 (AP-3 and BLOC-3 deficiency):
- Pulmonary fibrosis: Does not manifest until the third decade of life, presenting with ground-glass opacities, reticulation, and traction bronchiectasis on imaging, ultimately fatal without lung transplantation 1, 3, 4
- HPS1, HPS4, and AP3B1 genes are most strongly associated with pulmonary fibrosis development 1
HPS Type 2 (AP3B1 mutations):
- Immunodeficiency: Severe neutropenia, marked defects in antigen presentation and T-cell cytotoxicity, and recurrent pyogenic bacterial infections affecting respiratory tract, skin, and other organs 5, 7
- Accelerated phase: Can progress to hemophagocytic lymphohistiocytosis (HLH) with high fever, toxic appearance, lymphadenopathy, and hepatosplenomegaly—fatal without immediate chemotherapy and immunosuppression 5, 7
- Variable immunologic abnormalities including hypogammaglobulinemia, impaired delayed cutaneous hypersensitivity, impaired NK cell cytotoxicity, and decreased T-cell responses 5
BLOC-3 deficiency:
Diagnostic Approach
Initial Confirmation
- Platelet electron microscopy: Demonstrates absent or markedly reduced platelet dense granules, pathognomonic for HPS 1
- Gene sequencing: Identify the specific HPS subtype through molecular testing of HPS1-9, AP3B1, AP3D1, BLOC1S3, BLOC1S6, and DTNBP1 genes 1, 7
- Genetic subtyping directly determines prognosis and surveillance intensity, as pulmonary fibrosis risk and immunodeficiency presence are subtype-specific 7
Critical Diagnostic Pitfall
- Do not rely on normal screening immune function tests in HPS type 2: Immunologic abnormalities are variable and may not appear until the accelerated HLH phase develops 7
Management Strategy
HPS Type 2 Specific Management
- Monitor for HLH acceleration: Watch for acute presentations with high fever, toxic appearance, lymphadenopathy, and hepatosplenomegaly requiring immediate chemotherapy and immunosuppression 7
- Treat infections promptly: Pyogenic bacterial infections require aggressive early treatment 7
- Consider immunoglobulin replacement: If hypogammaglobulinemia develops during monitoring 7
Pulmonary Fibrosis Management (HPS Types 1,2,4)
- Pirfenidone: Antifibrotic therapy for HPS-related pulmonary fibrosis 3
- Lung transplantation: Definitive treatment for advanced pulmonary fibrosis 3
- Surveillance: Multidisciplinary monitoring beginning in early adulthood for early detection of pulmonary fibrosis in at-risk subtypes 3
Bleeding Management
- Avoid platelet transfusions for routine procedures: Platelets lack dense granules and are ineffective 6
- Desmopressin (DDAVP): May improve hemostasis in some patients 6
- Antifibrinolytic agents: Tranexamic acid or aminocaproic acid for bleeding episodes 6