BACKGROUND: Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease. CASE PRESENTATION: A 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics. CONCLUSIONS: Compound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital and Faculty of Medicine Jihlavská 20 625 00 Brno Czech Republic

Department of Pulmonary Diseases and Tuberculosis Masaryk University Faculty of Medicine and University Hospital Brno Czech Republic

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Huizing M, Helip-Wooley A, Westbroek W, Gunay-Aygun M, Gahl WA. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu Rev Genomics Hum Genet. 2008;9:359–386. doi: 10.1146/annurev.genom.9.081307.164303. PubMed DOI PMC

Gahl WA, Brantly M, Kaiser-Kupfer MI, Iwata F, Hazelwood S, Shotelersuk V, et al. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome) N Engl J Med. 1998;338(18):1258–1264. doi: 10.1056/NEJM199804303381803. PubMed DOI

McElvaney OJ, Huizing M, Gahl WA, O’Donovan P, Horan D, Logan PM, et al. Hermansky-Pudlak syndrome with a novel genetic variant in HPS1 and subsequent accelerated pulmonary fibrosis: significance for phenocopy diseases. Thorax. 2018;73:1085–1088. doi: 10.1136/thoraxjnl-2018-211920. PubMed DOI PMC

Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: report of two cases with histochemical studies. Blood. 1959;14:162–169. doi: 10.1182/blood.V14.2.162.162. PubMed DOI

Witkop CJ, Nuñez Babcock M, Rao GH, Gaudier F, Summers CG, Shanahan F, et al. Albinism and Hermansky-Pudlak syndrome in Puerto Rico. Bol Asoc Med P R. 1990;82(8):333–339. PubMed

Gahl WA, Brantly M, Troendle J, Avila NA, Padua A, Montalvo C, et al. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab. 2002;76(3):234–242. doi: 10.1016/S1096-7192(02)00044-6. PubMed DOI

Stenson PD, Mort M, Ball EV, Evans K, Hazden M, Heywood S, et al. The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–677. doi: 10.1007/s00439-017-1779-6. PubMed DOI PMC

Wei A, Yuan Y, Bai D, Ma J, Hao Z, Zhang Y, et al. NGS-based 100-gene panel of hypopigmentationidentifies mutations in Chinese Hermansky–Pudlak syndrome patients. Pigment Cell Melanoma Res. 2016;29:702–706. doi: 10.1111/pcmr.12534. PubMed DOI

Theunissen TEJ, Sallevelt SCEH, Hellebrekers DMEI, de Koning B, Hendrickx ATM, van den Bosch BJC, et al. Rapid resolution of blended or composite multigenic disease in infants by whole-exome sequencing. J Pediatr. 2017;182:371–374. doi: 10.1016/j.jpeds.2016.12.032. PubMed DOI

Hermos CR, Huizing M, Kaiser-Kupfer MI, Gahl WA. Hermansky-Pudlak syndrome type 1: gene organization, novel mutations, and clinical-molecular review of non-Puerto Rican cases. Hum Mutat. 2002;20:482. doi: 10.1002/humu.9097. PubMed DOI

Yousaf S, Shahzad M, Tasleem K, Sheikh SA, Tariq N, Sabbir AS, et al. Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population. Pigment Cell Melanoma Res. 2016;29(2):231–235. doi: 10.1111/pcmr.12438. PubMed DOI PMC

Abouelhoda M, Sobahy T, El-Kalioby M, Patel N, Shamseldin H, Monies D, et al. Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden. Genet Med. 2016;18:1244–1249. doi: 10.1038/gim.2016.37. PubMed DOI

Vicary GW, Vergne Y, Santiago-Cornier A, Young LR, Roman J. Pulmonary fibrosis in Hermansky-Pudlak syndrome. Ann Am Thorac Soc. 2016;13(10):1839–1846. PubMed PMC

Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA. 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. Chest. 2000;117(1):129–136. doi: 10.1378/chest.117.1.129. PubMed DOI

Lederer DJ, Kawut SM, Sonett JR, Vakiani E, Seward SL, Jr, White JG, et al. Successful bilateral transplantation for pulmonary fibrosis associated with the Hermansky-Pudlak syndrome. J Heart Lung Transplant. 2005;24:1697–1699. doi: 10.1016/j.healun.2004.11.015. PubMed DOI

El-Chemaly S, O'Brien KJ, Nathan SD, Weinhouse GL, Goldberg HJ, Connors JM, et al. Clinical management and outcomes of patients with Hermansky-Pudlak syndrome pulmonary fibrosis evaluated for lung transplantation. PLoS One. 2018;13(3):e0194193. doi: 10.1371/journal.pone.0194193. PubMed DOI PMC