Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome is a group of rare autosomal recessive disorders of lysosome related organelles, with oculocutaneous albinism, a platelet storage pool disorder with bleeding, and in some types pulmonary fibrosis and granulomatous colitis. It is caused by variants in at least 11 genes (HPS1 to HPS11).

The highest frequency is in northwest Puerto Rico (HPS-1, about 1 in 1800), and cases occur worldwide. Pulmonary fibrosis affects HPS-1, HPS-2 and HPS-4 patients, usually in the third to fourth decades, and is the main cause of death.

Pathophysiology. Defective biogenesis of lysosome related organelles impairs melanosomes (albinism), platelet dense granules (bleeding) and lamellar bodies in type II pneumocytes. Abnormal surfactant handling and ceroid lipofuscin accumulation drive alveolar epithelial injury, macrophage activation and fibrosis.

Pale skin and hair with variable pigmentation, nystagmus, reduced visual acuity and photophobia from birth, and easy bruising, epistaxis, prolonged bleeding after surgery or dental work, and heavy menstrual bleeding. Pulmonary fibrosis presents as progressive dyspnoea and dry cough, with clubbing and crackles. Colitis causes abdominal pain and bloody diarrhoea.

Respiratory failure, severe bleeding or acute abdominal complications need urgent care.

• Clinical diagnosis from albinism, a bleeding history and a family history, with confirmation by genetic testing (panel for HPS genes).
• Platelet electron microscopy showing absent dense bodies (the diagnostic test), and platelet aggregation studies with normal count and prolonged bleeding time.
• High resolution CT: reticular opacity, ground glass, peribronchial thickening and, later, honeycombing with a subpleural predominance in the lower zones.
• Lung function: restrictive pattern with low DLCO, and six minute walk test.
• Ophthalmological assessment, and endoscopy for colitis when symptoms exist.
• Screening bloods: full blood count, coagulation tests (normal).

Differential diagnosis.

• Idiopathic pulmonary fibrosis
• Other forms of albinism without pulmonary disease
• Chediak-Higashi syndrome (with immunodeficiency and neutropenia)
• Von Willebrand disease and other platelet function disorders
• Inflammatory bowel disease

• Pulmonary fibrosis: pirfenidone 801 mg three times daily after titration (267 mg three times daily for 1 week, 534 mg three times daily for the second week), which slowed decline in FVC in a controlled study in HPS-1, with liver function checks and sun protection. Nintedanib 150 mg twice daily is considered for progressive fibrosis.
• Supportive care: oxygen when PaO2 is 7.3 kPa or less, pulmonary rehabilitation, vaccination against influenza, pneumococcus and COVID-19, avoidance of smoking, and prompt treatment of infection.
• Bleeding: avoid aspirin and NSAIDs. Desmopressin 0.3 micrograms/kg intravenously (or 150 to 300 micrograms intranasally) before procedures, tranexamic acid 1 g orally three times daily (or 15 mg/kg) for mucosal bleeding and procedures, and platelet transfusion for major bleeding or surgery, as discussed with haematology.
• Eyes: low vision aids, tinted glasses, regular ophthalmology. Skin: sun protection, sunscreen and regular dermatology review for skin cancer.
• Colitis: mesalazine, with specialist agents added by gastroenterology.
• Lung transplantation for advanced fibrosis in suitable patients, with attention to bleeding risk.
• Genetic counselling and cascade testing.

Complications and prognosis. Fibrosis is usually progressive and fatal in the fourth to fifth decade in HPS-1. Other types have milder disease.

Monitoring. Spirometry, DLCO and walk test every 3 to 6 months, CT yearly, and haematology review for bleeding risk before any procedure.

Referral and escalation. Refer to a rare lung disease service, haematology, ophthalmology and genetics, and to a transplant centre for advanced fibrosis.