Hermansky-Pudlak syndrome with a novel genetic variant in HPS1 and 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 HPS1 gene. Of interest, this is the only described HPS type 1 patient with two different (compound heterozygote) splice site variants in HPS1 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.

Keywords: alpha1 antitrypsin deficiency; bronchiectasis; cystic fibrosis; interstitial fibrosis; lung transplantation; rare lung diseases.

Figure 1

Progressive HPS-associated fibrotic lung disease. Genetic sequencing revealed the first case of two different compound heterozygous splice site variants in the HPS1 gene, including a previously undescribed novel variant (panel A; †Exp. Splice Effect: as reported in literature: ND; Yes, i.e., splice site effect was demonstrated experimentally. ‡Using Human Splice Site Prediction by Neural Network, comparing wild-type sequence to variant sequence). Predicted Splice Site Scores are visualised as follows: green (high splice site prediction >80%), yellow (medium splice site prediction 50%–80%) and red (low splice site prediction <50%). The patient underwent monitoring with serial HRCT thorax imaging (panel B), spirometry with DLCO (panel C), FVC (panel E) and cardiopulmonary exercise testing (panel D). Despite brief improvement following commencement of pirfenidone (asterisk), steady decline in these indices over time can be observed. DLCO, diffusing capacity of the lung for carbon monoxide; EXP, experimental; FVC, forced vital capacity; HPS1, Hermansky-Pudlak syndrome gene; HRCT, high-resolution CT; ND, not done.