Kevin J O'Brien1, Jay Lozier2, Andrew R Cullinane3, Brigitte Osorio1, Khanh Nghiem2, Vladislav Speransky4, Wadih M Zein5, James C Mullikin6, Anne T Neff7, Karen L Simon8, May Christine V Malicdan9, William A Gahl10, Lisa R Young11, Bernadette R Gochuico12. 1. Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1205, USA. 2. Department of Laboratory Medicine, Clinical Center, NIH, 10 Center Drive, Bethesda, MD 20892-1508, USA. 3. 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. 4. National Institute of Biomedical Imaging and Bioengineering, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA. 5. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, 10 Center Drive, Bethesda, MD 20892-1860, USA. 6. NIH Intramural Sequencing Center, NIH, 5625 Fishers Lane, Rockville, MD 20852, USA. 7. Department of Hematology/Medical Oncology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. 8. Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, Bethesda, MD 20892-1851, USA. 9. 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. 10. 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. 11. 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. 12. Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, Bethesda, MD 20892-1851, USA. Electronic address: gochuicb@mail.nih.gov.
Abstract
PURPOSE: 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. RESULTS: 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. CONCLUSIONS: 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. Published by Elsevier Inc.
PURPOSE: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. RESULTS: 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. CONCLUSIONS: 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. Published by Elsevier Inc.
Entities:
Keywords:
Christmas disease; Factor IX deficiency; Hemophilia B; Hermansky-Pudlak syndrome; Oculocutaneous albinism; Platelet storage pool disorder
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