title: Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism.
abstract: Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism.
  
  
  
  The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions.
  
  
  
  This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient with Hermansky-Pudlak syndrome subtype 6.
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1205, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: O'Brien
authors.affiliation: Department of Laboratory Medicine, Clinical Center, NIH, 10 Center Drive, Bethesda, MD 20892-1508, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Lozier
authors.affiliation: Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, Bethesda, MD 20892-1851, USA; Department of Anatomy, College of Medicine, Howard University, 520 W St., NW, Washington, DC 20059, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1205, USA.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Osorio
authors.affiliation: Department of Laboratory Medicine, Clinical Center, NIH, 10 Center Drive, Bethesda, MD 20892-1508, USA.
authors.forename: Khanh
authors.initials: K
authors.lastname: Nghiem
authors.affiliation: National Institute of Biomedical Imaging and Bioengineering, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Speransky
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, 10 Center Drive, Bethesda, MD 20892-1860, USA.
authors.forename: Wadih M
authors.initials: WM
authors.lastname: Zein
authors.affiliation: NIH Intramural Sequencing Center, NIH, 5625 Fishers Lane, Rockville, MD 20852, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Department of Hematology/Medical Oncology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Neff
authors.affiliation: Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, Bethesda, MD 20892-1851, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Simon
authors.affiliation: Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, Bethesda, MD 20892-1851, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1205, USA; Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, Bethesda, MD 20892-1851, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Division of Pediatric Allergy, Immunology, and Pulmonary Medicine, Vanderbilt University School of Medicine, 2200 Children's Way, 11215 Doctors' Office Tower, Nashville, TN 37232-9500, USA; Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine,1161 21st Ave. South, T-1217 Medical Center North, Nashville, TN 37232-9500, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.affiliation: Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, Bethesda, MD 20892-1851, USA. Electronic address: gochuicb@mail.nih.gov.
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
mesh_terms: D000328:Adult; D016115:Albinism, Oculocutaneous / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D002836:Hemophilia B / Q000235:genetics* / Q000473:pathology; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype
chemical_list: C493901:HPS6 protein, human; D047908:Intracellular Signaling Peptides and Proteins
keywords: Christmas disease; Factor IX deficiency; Hemophilia B; Hermansky-Pudlak syndrome; Oculocutaneous albinism; Platelet storage pool disorder