Pulmonary Function and High-Resolution CT Findings in Patients With an Inherited Form of Pulmonary Fibrosis, Hermansky-Pudlak Syndrome, Due to Mutations in HPS-1

Brantly, Mark; Avila, Nilo A.; Shotelersuk, Vorasuk; Lucero, Cynthia; Huizing, Marjan; Gahl, William A.

doi:10.1378/chest.117.1.129

Cited by 169 publications

(159 citation statements)

References 29 publications

Supporting

Mentioning

156

Contrasting

Unclassified

Order By: Relevance

“…As the disease progresses, the predominant radiographic findings are seen within the lung periphery and progress toward the central portion of the lung. Characteristic abnormalities include ground-glass opacities, reticulation of interstitial spaces, and, in advanced disease, loss of lung volume, honeycombing, and traction bronchiectasis (15,59,60).…”

Section: Monitoring Progression Of Pulmonary Fibrosismentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Section: Monitoring Progression Of Pulmonary Fibrosismentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Baseline and follow-up HRCT scans were read independently by two chest radiologists using a previously described quantitative scale (14,15). Discrepant readings were re-reviewed by both radiologists to determine consensus readings.…”

Section: Hrctmentioning

confidence: 99%

Early Interstitial Lung Disease in Familial Pulmonary Fibrosis

Rosas¹,

Ren²,

Avila³

et al. 2007

Am J Respir Crit Care Med

Self Cite

154

158

View full text Add to dashboard Cite

Rationale: Identification of early, asymptomatic interstitial lung disease (ILD) in populations at risk of developing idiopathic pulmonary fibrosis (IPF) may improve the understanding of the natural history of IPF. Objectives: To determine clinical, radiographic, physiologic, and pathologic features of asymptomatic ILD in family members of patients with familial IPF. Methods: One hundred sixty-four subjects from 18 kindreds affected with familial IPF were evaluated for ILD. Bronchoalveolar lavage fluid cells were analyzed using flow cytometry. Lung biopsies were performed in six subjects with asymptomatic ILD. Measurements and Main Results: High-resolution computed tomography abnormalities suggesting ILD were identified in 31 (22%) of 143 asymptomatic subjects. Subjects with asymptomatic ILD were significantly younger than subjects with known familial IPF (P , 0.001) and significantly older than related subjects without lung disease (P , 0.001). A history of smoking was identified in 45% of subjects with asymptomatic ILD and in 67% of subjects with familial IPF; these percentages were significantly higher than that of related subjects without lung disease (23%) (P 5 0.02 and P , 0.001, respectively). Percentages of activated CD4 1 lymphocytes were significantly higher in bronchoalveolar lavage fluid cells from subjects with asymptomatic ILD compared with related subjects without lung disease (P , 0.001). Lung biopsies performed in subjects with asymptomatic ILD revealed diverse histologic subtypes. Conclusions: Asymptomatic ILD in individuals at risk of developing familial IPF can be identified using high-resolution computed tomography scan of the chest, especially in those with a history of smoking. Lung biopsies from individuals in this cohort with early asymptomatic lung disease demonstrate various histologic subtypes of ILD.

show abstract

“…Therefore, these results suggested that patients 88 and 156 suffer from HPS due to mutations causing BLOC-2 deficiency, and that patients 45, 94 and 128 suffer from HPS due to BLOC-3 deficiency. Based on reported differences in the severity of HPS disease caused by BLOC-2 deficiency (in HPS-3, -5 or -6 [8,11,[29][30][31][32]) or BLOC-3 deficiency (in HPS-1 or -4 [18][19][20][21][22][23]), one would then expect that patients 88 and 156 should suffer from a mild form of HPS and that patients 45, 94 and 128 should be at a higher risk of developing pulmonary fibrosis or GI disease. Unfortunately, only two of these patients (88 and 45) were examined at an age in which the validity of these predictions could begin to be evaluated: at the time of their last evaluation at the NIH Clinical Center, patients 88 (age 40 years), 94 (age 2 years), 128 (age 2 years) and 156 (age 19 years) had no signs of interstitial lung disease of GI disease, while patient 45 (age 35 years) presented with a history of GI disease but no interstitial lung disease.…”

Section: Analysis Of Samples From Hps Patients Of Unknown Genetic Lesmentioning

confidence: 99%

“…Clinical characterization of some HPS types has begun to lend support to this notion. Thus, both HPS-1 and -4, and not other HPS types, are associated with increased risks of developing pulmonary fibrosis (which can be fatal) and gastro-intestinal (GI) manifestations such as granulomatous colitis [18][19][20][21][22][23], although that may not be the case for HPS-1 patients from a Swiss isolate [3]. HPS-2, and not the other HPS types, is associated with recurrent infections due to chronic neutropenia and other deficiencies in the innate immune system [24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

Nazarian

Huizing

Helip-Wooley

et al. 2008

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

Hermansky-Pudlak syndrome (HPS) comprises a constellation of human autosomal recessive disorders characterized by albinism and platelet storage pool deficiency. At least eight types of HPS have been defined based on the identity of the mutated gene. These genes encode components of four ubiquitously expressed protein complexes, named Adaptor Protein (AP)-3 and Biogenesis of Lysosome-related Organelles Complex (BLOC)-1 through -3. In patients of Puerto Rican origin, the molecular diagnosis can be based on analysis of two founder mutations. On the other hand, identification of the HPS type in other patients relies on the sequencing of all candidate genes. In this work, we have developed a biochemical assay to minimize the number of candidate genes to be sequenced per patient. The assay consists of immunoblotting analysis of extracts prepared from skin fibroblasts, using antibodies to one subunit per protein complex. The assay allowed us to determine which complex was defective in each of a group of HPS patients with unknown genetic lesions, thus subsequent sequencing was limited to genes encoding the corresponding subunits. Because no mutations within the two genes encoding BLOC-3 subunits could be found in two patients displaying reduced BLOC-3 levels, the possible existence of additional subunits was considered. Through sizeexclusion chromatography and sedimentation velocity analysis, the native molecular mass of BLOC-3 was estimated to be 140 ± 30 kDa, a value most consistent with the idea that BLOC-3 is a HPS1•HPS4 heterodimer (∼156 kDa) albeit not inconsistent with the putative existence of a relatively small third subunit.

show abstract

Pulmonary Function and High-Resolution CT Findings in Patients With an Inherited Form of Pulmonary Fibrosis, Hermansky-Pudlak Syndrome, Due to Mutations in HPS-1

Cited by 169 publications

References 29 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Early Interstitial Lung Disease in Familial Pulmonary Fibrosis

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

Contact Info

Product

Resources

About