Chest
Volume 117, Issue 1, January 2000, Pages 129-136
Journal home page for Chest

Clinical Investigations
TECHNIQUES
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

https://doi.org/10.1378/chest.117.1.129Get rights and content

Objective

To describe and correlate pulmonary functionand high-resolution CT (HRCT) scan scores in individuals with a highrisk for development of pulmonary fibrosis, ie, Hermansky-Pudlak syndrome (HPS) patients with mutations in theHPS-1gene.

Design

Cross-sectionalanalysis of consecutive, eligible patients.

Patients

Thirty-eight HPS inpatients at the National Institutes of Health Clinical Center with HPS-1mutations.

Results

Thirty-seven patients were Puerto Rican andexhibited the typical 16-base pair (bp) duplication in exon 15 ofHPS-1. One non-Puerto Rican was homozygous for a differentmutation (intervening sequence 17 −2 A→C) previously reported in theHPS-1gene; he died at age 35 of pulmonary insufficiency.For the 23 patients who had pulmonary symptoms, the mean age of onsetwas 35 years. For all 38 patients (mean age, 37 ± 2 years), the meanFVC was 71% of predicted; the mean FEV1, 76%; mean totallung capacity (TLC), 72%; mean vital capacity (VC), 68%; and meandiffusing capacity of the lung for carbon monoxide (Dlco),72%. When patients were grouped according to the extent of theirreduction in FVC, the other four pulmonary function parameters followedthe FVC. Seventeen patients had abnormal chest radiographs, and 31(82%) had abnormal HRCT scans of the chest, for which a scoring systemof 0 (normal) to 3 (severe fibrosis) is presented. The mean ± SEMHRCT score for 38 patients was 1.30 ± 0.17. HRCT scores correlatedinversely with FVC and Dlco.

Conclusions

Mutations in the HPS-1gene, whether or not they involvethe typical 16-bp duplication seen in Puerto Rican patients, areassociated with fatal pulmonary fibrosis. In affected patients, the FVC, FEV1, TLC, VC, and Dlco fall in concert, and this functional deficit correlates with HRCT scan evidence ofprogression of interstitial lung disease.

Section snippets

Patients

All the subjects were enrolled in a protocol approved by the National Institute of Child Health and Human Development Institutional Review Board and all gave written informed consent. HPS was diagnosed based on the presence of oculocutaneous albinism and a bleeding diathesis; the diagnosis was confirmed on molecular grounds. To be included in this data analysis, patients were required to be adults admitted to the National Institutes of Health (NIH) Clinical Center, to have mutations in HPS-1,

Patient Population

Patient characteristics are shown in Table 1. The 38 HPS patients in this study ranged in age from 19 to 57 years, with a mean age of 37 years. Eighteen patients were men, and 37 were of Puerto Rican ancestry. All 37 Puerto Rican patients exhibited homozygosity for the typical 16-bp duplication in exon 15 of HPS-1 (data not shown). Only 1 of the 38 patients smoked at the time of admission, but 5 had smoked sometime in their lives. The five had smoking histories estimated to be 2, 4, 14, 17, and

Discussion

Recent molecular advances allow clinical evaluation of HPS patients based on their genetic loci and individual mutations. The most critical aspect of this evaluation involves the life-threatening pulmonary disease of HPS. Previous studies of pulmonary function in this disorder have included relatively few individuals,6, 2324, 2526, 27 or have concentrated on pulmonary lavage findings.7 We performed an intensive, inpatient investigation of adults who had molecularly defined mutations in HPS-1,

ACKNOWLEDGMENTS

The authors appreciate the excellent work of Hilda Cardona and the other nurses of the 8 W and 9 W wards and the pulmonary function unit of the NIH Clinical Center. This study would not have been possible without the assistance of the HPS Network and its presidents, based in Puerto Rico (Carmelo Almodovar) and the mainland United States (Donna Appell).

References (36)

  • EC Dell'Angelica et al.

    Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the β3A subunit of the AP-3 adaptor

    Mol Cell

    (1999)
  • V Shotelersuk et al.

    Hermansky-Pudlak syndrome: models for intracellular vesicle formation

    Mol Genet Metab

    (1998)
  • CJ Witkop et al.

    Albinism

  • CG Summers et al.

    Hermansky-Pudlak syndrome: ophthalmic findings

    Ophthalmology

    (1988)
  • RA King et al.

    Albinism

  • CJ Witkop et al.

    Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome

    Am J Hematol

    (1987)
  • KR Harmon et al.

    Pathogenesis of pulmonary fibrosis: platelet-derived growth factor precedes structural alterations in the Hermansky-Pudlak syndrome

    J Lab Clin Med

    (1994)
  • RA Schinella et al.

    Hermansky-Pudlak syndrome with granulomatous colitis

    Ann Intern Med

    (1980)
  • Cited by (0)

    View full text