Hermansky-Pudlak syndrome with a novel genetic variant inHPS1and subsequent accelerated pulmonary fibrosis: significance for phenocopy diseases

Abstract

The Hermansky-Pudlak syndrome (HPS) is a collection of autosomal-recessive disorders characterised by tyrosinase-positive oculocutaneous albinism (OCA), bleeding diatheses and, in selected individuals, early-onset accelerated pulmonary fibrosis, neutropaenia and granulomatous colitis. We describe a young man who presented following a self-directed literature review prompted by severe bleeding complications following minor surgical and dental procedures in the context of OCA. HPS was clinically suspected, with subsequent genetic testing confirming biallelic mutations in the gene. Of interest, this is the only described HPS type 1 patient with two different (compound heterozygote) splice site variants in In addition to detailing a novel genetic result and outlining the progressive clinical course of disease in this case, we discuss the management of HPS, the prognostic value of subtype analysis and the technical difficulties relating to transplantation in the case of HPS-associated advanced pulmonary fibrosis. This case also illustrates the concept of lung phenocopy relationships and the potential for elucidating the pathogenesis of more common pulmonary disorders by studying genetic diseases that result in similar phenotypes. Furthermore, it re-emphasises the importance of the patient voice, particularly with regard to complex diagnoses and rare diseases.

Novel genetic variant of HPS1 gene in Hermansky-Pudlak syndrome with fulminant progression of pulmonary fibrosis: a case report

“…The most common pathogenic variants of HPS1 gene are nonsense/missense or small deletions. Pulmonary fibrosis is seen in approximately one half of carriers of HPS1 and HPS4 gene mutations [2, 3, 6]. However, other HPS1 gene variants are associated with milder symptoms like albinism, nystagmus, hypopigmentation, foveal hypoplasia or absent nails [7].…”

“…Furthermore, the processed variants/indels were matched to the virtual panel of genes including HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN . The virtual panel was created based on the literature review [1–3]. Exome sequencing identified a compound heterozygous genotype in the HPS1 gene (NM_000195.3) in the proband: 1) pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon, associated with HPS; and 2) previously undescribed nonsense variant, c.1507C > T; p.(Gln503*), resulting in a premature stop codon, implying a loss of 197 amino acids or more likely, nonsense-mediated decay of the mRNA degradation (Fig.…”

“…The HPS spectrum includes ten disorders (HPS-1 to HPS-10). Homozygous or compound heterozygous mutations in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease [1–3]. The disease was described by two Czech hematologists František Heřmanský and Pavel Pudlák in 1959 [4].…”

Hermansky–Pudlak Syndrome

“…Proposed additional contributing factors in idiopathic pulmonary fibrosis (IPF) such as viral infections and chronic aspiration have not been studied in HPS. 47 Previous studies suggest that the pathogenesis of PF in HPS is related to a defect that alters alveolar epithelial cell function, 48 with fibrotic signals subsequently transduced to macrophages and fibroblasts to promote the accumulation of extracellular matrix and fibrotic remodeling. [49][50][51]…”

Hermansky–Pudlak syndrome: Mutation update

“… aa This HPS1 variant was identified in a subject with of Irish descent with HPS clinical features and accelerated pulmonary fibrosis. He was compound heterozygous for c.1744–2A>C (predicted to cause exon skipping [Oetting & King, 1999]) and c.1857+2T>C (predicted to result in use of alternative intronic splice site 4 bp into intron 18, resulting in a frameshift of the coding region; Table S2; McElvaney et al, 2018). …”