Hermansky-Pudlak Syndrome (HPS) is a rare genetic disorder with autosomal recessive inheritance. HPS has been reported worldwide with a prevalence of 1-2 per 1,000,000 individuals worldwide but is highly concentrated in Puerto Rico, where an estimated ~50% of cases are diagnosed. Clinical features include oculocutaneous albinism, platelet dysfunction resulting in a bleeding diathesis as well as granulomatous colitis in a subset of HPS patients. There are 10 different forms of the disease that have been described and each are due to different mutations in HPS associated genes. The HPS-1 form is the most common and associated with lung disease but pulmonary fibrosis can occur in subtypes 1, 2, and 4. The pulmonary fibrosis itself resembles idiopathic pulmonary fibrosis (IPF) but typically occurs at a much younger age with symptoms often presenting in the early 30s for afflicted patients.
The proteins encoded by HPS genes are involved in the biogenesis of lysosome-related organelle complexes (BLOCs). These lysosome-related organelles (LROs) are involved in cellular trafficking of proteins in the cell including to melanosomes and platelet dense granules. How these intracellular trafficking defects relate to the lung fibrosis aspects of the disease is an area of ongoing investigation. Naturally-occurring and transgenic animals with HPS mutations are an actively utilized tool to understand disease pathogenesis. By using these models as well as tissue from patients with HPS mutations, it is the hope that targeted therapies can be developed to treat this condition.
The diagnosis of HPS should be made clinically and can be confirmed by testing for the platelet abnormality via electron microscopy to confirm the absence of platelet dense bodies. Identification of biallelic pathogenic variants in AP3B1, AP3D1, BLOC1S3, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 also confirms the diagnosis if clinical features are inconclusive. Lung biopsies are discouraged and can be dangerous secondary to the bleeding diathesis.
Through studies conducted at the National Institutes of Health (NIH) since the mid-90s, many advances have been made in HPS, including identification of the genetic basis. However, like many rare lung diseases, there are no FDA-approved therapies for HPS or the associated pulmonary fibrosis at this time. Treatment is largely supportive and geared towards sun protection and treatment of visual impairment and other systemic manifestations. Pulmonary fibrosis should be actively monitored and regularly assessed as it represents the leading cause of death in HPS patients with a ~10-year life expectancy once the diagnosis of restrictive lung disease is made. Lung transplantation has been performed successfully for HPS and appropriate patients with end-stage pulmonary fibrosis should be referred for transplant evaluation. Because of the recognizable clinical features of HPS and the support and advocacy of the HPS network, the hope is that preventative approaches and/or early disease treatment strategies can be developed over time.
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Four Facts About Hermansky-Pudlak Syndrome
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