What is the management and treatment approach for a patient with suspected Hermansky-Pudlak syndrome?

Hermansky-Pudlak Syndrome: Management and Treatment

Diagnostic Confirmation

Confirm HPS diagnosis through genetic testing to identify the specific subtype (HPS1-9), as this directly determines prognosis, surveillance intensity, and risk stratification for life-threatening complications. 1, 2

• Obtain platelet electron microscopy demonstrating absent or reduced platelet dense bodies, which provides the definitive diagnostic criterion 1, 3, 4
• Perform gene sequencing targeting HPS1, HPS3, HPS4, AP3B1, HPS5, HPS6, and less commonly AP3D1, BLOC1S3, BLOC1S6, DTNBP1 1, 3
• HPS1, HPS4, and AP3B1 subtypes carry the highest risk for fatal pulmonary fibrosis, typically manifesting in the third decade of life 1, 3
• HPS type 2 specifically presents with severe neutropenia, immunodeficiency, and risk of hemophagocytic lymphohistiocytosis (HLH), which is fatal without immediate chemotherapy and immunosuppression 2

Bleeding Diathesis Management

Avoid all antiplatelet agents (aspirin, NSAIDs including ketorolac/Toradol, clopidogrel) due to the underlying platelet storage pool deficiency. 3, 5

• Use acetaminophen (paracetamol) as the primary analgesic for pain control 6
• Administer desmopressin (DDAVP) for minor bleeding episodes or prophylactically before dental procedures 3
• Transfuse platelets for major bleeding or surgical procedures, recognizing that platelet dysfunction limits effectiveness 3, 5
• Avoid intramuscular injections and contact sports to minimize bleeding risk 3

Pulmonary Fibrosis Surveillance and Management

Begin annual pulmonary function testing (PFTs) with forced vital capacity (FVC) and diffusing capacity (DLCO) starting at age 18-20 years for HPS1, HPS4, and AP3B1 subtypes. 1, 3

• Obtain high-resolution chest CT every 1-2 years once pulmonary fibrosis is detected 3
• Pirfenidone showed no efficacy in a randomized controlled trial for HPS-1 pulmonary fibrosis and cannot be recommended 7
• Refer for lung transplantation evaluation when FVC declines below 60% predicted or DLCO below 40% predicted, as this is the only effective treatment for progressive pulmonary fibrosis 3, 7
• Avoid environmental exposures that accelerate lung injury, including smoking, occupational dust, and pulmonary infections 3

Immunodeficiency Management (HPS Type 2 Only)

Monitor HPS type 2 patients closely for signs of accelerated phase HLH: high fever, toxic appearance, lymphadenopathy, hepatosplenomegaly, cytopenias, and elevated ferritin. 2

• Treat pyogenic bacterial infections (respiratory tract, skin) promptly with appropriate antibiotics 2
• Consider immunoglobulin replacement therapy if hypogammaglobulinemia develops 2
• Initiate immediate chemotherapy and immunosuppression if HLH develops, as this complication is uniformly fatal without treatment 2
• Do not rely on screening immunologic tests to exclude immunodeficiency, as abnormalities may not appear until the accelerated phase 2

Gastrointestinal Disease Management

Screen for granulomatous colitis with colonoscopy if patients develop chronic diarrhea, abdominal pain, or hematochezia. 3, 5, 8

• Treat granulomatous colitis similarly to inflammatory bowel disease with aminosalicylates, corticosteroids, or immunomodulators as needed 8
• Monitor for ceroid accumulation in the gastrointestinal tract, which can cause malabsorption 4, 8

Ophthalmologic Management

Refer all HPS patients to ophthalmology for management of nystagmus, decreased visual acuity, and photophobia from oculocutaneous albinism. 1, 3, 5

• Prescribe tinted lenses and low-vision aids to improve visual function 3
• Monitor for progressive vision loss throughout life 1

Critical Pitfalls to Avoid

• Never administer NSAIDs or antiplatelet agents, as the platelet storage pool deficiency causes severe bleeding diathesis 3, 5
• Do not delay lung transplantation referral once pulmonary fibrosis progresses, as median survival after diagnosis is 10-15 years in HPS1 3, 7
• Do not miss the accelerated HLH phase in HPS type 2, which requires immediate recognition and treatment to prevent mortality 2
• Avoid assuming normal immune function in HPS type 2 based on initial screening tests, as immunologic abnormalities are variable 2

Population-Specific Considerations

• Northwest Puerto Rican and Ashkenazi Jewish populations have higher HPS prevalence due to founder mutations 1, 3
• Screen family members of affected individuals, as HPS follows autosomal recessive inheritance 3, 5