Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant

Abstract

Heřmanský-Pudlák syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS-6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome-wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS. Clinical Trial registration: Registrar: ClinicalTrials.gov Website: www.clinicaltrials.gov Registration Numbers: NCT00001456 and NCT00084305.

Keywords: Heřmanský-Pudlák syndrome; oculocutaneous albinism; platelet delta granules.

© 2018 Wiley Periodicals, Inc.

Figures

Figure 1

Clinical and molecular features of patient with Hermansky-Pudlak syndrome type 6. (A) Pedigree shows proband (arrow) with Hermansky-Pudlak syndrome-6 (HPS-6) and consanguinity. (B) Anterior segment photos show absent iris transillumination defects in a normal volunteer (left panel). Mild transillumination defects, seen as dark red scattered across the iris in both the right (middle panel) and left (right panel) eyes were present in this patient with HPS-6. (C) Wide field images of the retina demonstrate normal pigmentation in a healthy volunteer (left panel) in contrast to the minimally pigmented peripheral retina with visible choroidal vasculature (black arrows) due to lack of pigmentation in the patient’s right and left eyes (middle and right panels, respectively). (D) Optical coherence tomography shows a normal fovea in the healthy volunteer (left panel), while the patient’s fovea shows grade 3 foveal hypoplasia with loss of the foveal depression (white arrow), no outer segment lengthening relative to the parafoveal outer nuclear layer, and no extrusion of the plexifom layers (middle and right panels). (E) Representative platelets from this patient with absent dense granules are shown by whole mount electron microscopy (left panel; size bar = 800 nm) and normal alpha granules by thin-section transmission electron microscopy (right panel; size bar = 2 um). (F) Representative high-resolution computed tomography scan image of the chest reveals right juxtapleural linear and nodular atelectasis (solid white arrow) without evidence of interstitial lung disease. (G, H) Expression of HPS6 mRNA and HPS6 protein in this patient’s dermal fibroblasts is significantly reduced compared to that in cells from two normal controls or three patients with HPS-1. Western blots for HPS6, HPS1, HPS 4 and beta actin are shown. Open arrow indicates band corresponding to HPS1 protein.