Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

Keywords: Hermansky–Pudlak syndrome; genetics; oculocutaneous albinism; pulmonary fibrosis.

Figure 1.

Lysosome-related organelles (LROs) are a group of cell type–specific subcellular compartments that share some features with endosomes and lysosomes, but also develop unique properties as they harbor specialized cargoes. Many of the clinical manifestations of Hermansky–Pudlak syndrome (HPS) are explained by abnormalities in the formation and trafficking of LROs, including albinism (melanosomes), bleeding (platelet-dense granules), and pulmonary fibrosis (likely related at least in part to abnormal lamellar body genesis in type II alveolar epithelial cells).

Figure 2.

Examples of chest computed tomographic findings in subjects with Hermansky–Pudlak syndrome (HPS). (A) A scan of a 50-year-old patient with HPS-1 shows mild changes consistent with subpleural infiltrates. (B) A scan of a 41-year-old patient with central infiltrates. (C) Ground-glass opacification. (D) Scans of a 31-year-old patient with mid- to upper lung infiltrates as well as subpleural honeycombing. The images shown are from patients who provided consent in the Rare Lung Diseases Consortium HPS study under Vanderbilt University IRB protocol number 150104.