Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease

Abstract

Pulmonary fibrosis develops in Hermansky-Pudlak syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factor-β1 and interleukin-17A correlated with severity of HPS-2 ILD. These data show that children and young adults with HPS-2 and functional defects of the AP-3 complex are at risk for ILD and pulmonary fibrosis.

Figure 1

Representative transmission electron micrographs from a subject with HPS-2 and severe interstitial lung disease. (A) and (B) show hyperplasia of type II cells (solid large arrows) with lamellar bodies (open large arrows) in the alveolar interstitial space from subject 1. Some type II cells have acicular spaces (small arrows) in the cytoplasm. Myofibroblasts (*) and collagen fiber bundles (C) are identified in the alveolar interstitium (C). Some areas of the lung contain capillaries with regional thickening of the basement membrane (arrowhead) (D).

Figure 2

Representative computed tomography scan images from two children with HPS-2 and severe interstitial lung disease. (A) shows severe bilateral ground glass opacities, thickening of interlobular septa and pulmonary fibrosis at the level of the carina for subject 1 at 8 years of age. A computed tomography scan image at the same level shows mild improvement in infiltrates (arrows) at 14 years of age (B). (C) shows extensive bilateral ground glass opacities when subject 4 was 4 years of age. A coronal CT scan image demonstrates diffuse ground glass infiltrates and interstitial reticulations (open arrows) in subject 4 (D).

Figure 3

Representative computed tomography and HRCT scan images from two adult brothers with HPS-2 and interstitial lung disease. A computed tomography and HRCT scan image in the prone position (A and B, respectively) show mild bilateral ground glass opacities (arrows) and interstitial reticulations (open arrows) in subject 2 at the age of 27 years. C and D demonstrate computed tomography and prone HRCT scan images from subject 3 when he was 22 years of age. Mild ground glass opacities (arrows) are present in the right middle lobe.