title: BK virus encephalopathy and sclerosing vasculopathy in a patient with hypohidrotic ectodermal dysplasia and immunodeficiency.
abstract: Human BK polyomavirus (BKV) is reactivated under conditions of immunosuppression leading most commonly to nephropathy or cystitis; its tropism for the brain is rare and poorly understood. We present a unique case of BKV-associated encephalopathy in a man with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) due to IKK-gamma (NEMO) mutation, who developed progressive neurological symptoms. Brain biopsy demonstrated polyomavirus infection of gray and white matter, with predominant involvement of cortex and distinct neuronal tropism, in addition to limited demyelination and oligodendroglial inclusions. Immunohistochemistry demonstrated polyoma T-antigen in neurons and glia, but expression of VP1 capsid protein only in glia. PCR analysis on both brain biopsy tissue and cerebrospinal fluid detected high levels of BKV DNA. Sequencing studies further identified novel BKV variant and disclosed unique rearrangements in the noncoding control region of the viral DNA (BKVN NCCR). Neuropathological analysis also demonstrated an unusual form of obliterative fibrosing vasculopathy in the subcortical white matter with abnormal lysosomal accumulations, possibly related to the patient's underlying ectodermal dysplasia. Our report provides the first neuropathological description of HED-ID due to NEMO mutation, and expands the diversity of neurological presentations of BKV infection in brain, underscoring the importance of its consideration in immunodeficient patients with unexplained encephalopathy. We also document novel BKVN NCCR rearrangements that may be associated with the unique neuronal tropism in this patient.
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Armine
authors.initials: A
authors.lastname: Darbinyan
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, MD, USA.
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.|Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.|Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Icahn 9-20E, New York, 10029, NY, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Holland
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, MD, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ryschkewitsch
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, MD, USA.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monaco
authors.affiliation: Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Naidich
authors.affiliation: Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Bederson
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Malaczynska
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Gordon
authors.affiliation: Department of Medicine - Allergy & Immunology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Fowkes
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA. nadejda.tsankova@mssm.edu.|Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Icahn 9-20E, New York, 10029, NY, USA. nadejda.tsankova@mssm.edu.
authors.forename: Nadejda M
authors.initials: NM
authors.lastname: Tsankova
mesh_terms: D000328:Adult; D001739:BK Virus / Q000235:genetics; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D001927:Brain Diseases / Q000150:complications* / Q000276:immunology / Q000473:pathology; D053358:Ectodermal Dysplasia 1, Anhidrotic / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000150:complications* / Q000235:genetics / Q000473:pathology; D008297:Male; D027601:Polyomavirus Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology
chemical_list: D051550:I-kappa B Kinase
keywords: BK virus; Ectodermal dysplasia; Encephalopathy; Fibrosing vasculopathy; HED-ID; IKK-gamma; NF-kappa-B essential modulator (NEMO); Polyomavirus