ADOPTING ORPHAN DISEASES RARE INTERSTITIAL LUNG DISEASES

adoptingorphandiseaseskapak

HERMANSKY-PUDLAK SYNDROME

Merve Erçelik

Süleyman Demirel University, Faculty of Medicine, Department of Chest Diseases, Isparta, Türkiye

Erçelik M. Hermansky-Pudlak Syndrome. In: Altınışık G, McCormack FX, editors. Adopting Orphan Diseases: Rare Interstitial Lung Diseases. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.123-133.

ABSTRACT

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive, multisystemic disorder characterized primarily by oculocutaneous albinism, bleeding tendencies, and variable involvement of other organs including lungs, colon, and immune system. Globally, HPS has an estimated prevalence between 1 in 500,000 and 1 in 1,000,000, although it is notably higher (1 in 1,800) in northwestern Puerto Rico, particularly for the HPS-1 subtype. Research in Germany has indicated that up to 35% of individuals with albinism may have a milder form of HPS, highlighting the potential benefit of broader screening efforts. HPS arises from mutations in 11 distinct genes responsible for proteins involved in lysosome-related organelle (LRO) biogenesis, resulting in disrupted protein trafficking and impaired organelle function. Each of the 11 HPS subtypes corresponds to specific genetic mutations but shares overlapping clinical manifestations. Among these, HPS-1 is recognized as the most severe subtype. Universal clinical features across all subtypes include tyrosinase-positive oculocutaneous albinism and varying degrees of platelet dysfunction leading to bleeding complications. Certain subtypes, notably HPS-1, HPS-2, and HPS-4, may additionally present severe complications such as pulmonary fibrosis, granulomatous colitis, immunodeficiency, or neurodegenerative changes. Pulmonary fibrosis, particularly prominent in the HPS-1 subtype, is the leading cause of mortality in these patients.

The onset of pulmonary fibrosis typically occurs in middle adulthood (30–40 years) in HPS-1 and HPS-4, while presenting earlier in childhood or young adulthood in HPS-2. Diagnosis of pulmonary fibrosis in HPS typically relies on high-resolution computed tomography (HRCT). Early-stage disease commonly manifests as basal, subpleural lung changes, progressing to bilateral reticular patterns, septal thickening, and, in advanced stages, loss of lung volume, honeycombing, and traction bronchiectasis. The radiological appearance of HPS-related fibrosis differs notably from idiopathic pulmonary fibrosis, particularly due to characteristic ground-glass opacities. The clinical diagnosis of HPS is based on identifying skin and hair hypopigmentation, distinctive ocular findings, and electron microscopy demonstrating absent platelet dense bodies. Genetic sequencing can confirm the diagnosis and identify the specific subtype. Despite trials of antifibrotic treatments, lung transplantation remains the sole definitive therapy for pulmonary fibrosis in HPS. Management strategies for other manifestations of the disease depend on the specific organ involved, and routine annual evaluations are generally advised. Emerging therapies, including gene therapy and gene editing, hold promise for future treatment.

Keywords: Hermansky-Pudlak syndrome; Albinism; Pulmonary fibrosis; Interstitial lung diseases; Rare interstitial lung diseases

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