title: Monozygotic twin pair showing discordant phenotype for X-linked thrombocytopenia and Wiskott-Aldrich syndrome: a role for epigenetics?
abstract: Despite our increasing characterization of the molecular basis for many primary immunodeficiency states, significant heterogeneity in clinical and immunological phenotype exists. Epigenetic alterations have been implicated in the pathogenesis of immune dysregulation and may provide a unique paradigm to help us understand the phenotypic heterogeneity in primary immunodeficiency. The occurrence of X-linked thrombocytopenia (XLT) and Wiskott-Aldrich syndrome (WAS) in monozygotic twins is a rare occurrence which allows for the exploration of epigenetic alterations and associated phenotypic heterogeneity. We describe a pair of monozygotic twin brothers with a missense mutation in the WAS gene consistent with reduced expression of the WAS protein, a XLT phenotype, and a good prognosis. Despite this genotype and anticipated mild phenotype in both twins, a discordant phenotype has evolved in which one twin demonstrates asymptomatic thrombocytopenia and the other symptomatic thrombocytopenia, infectious complications, and autoimmunity. Characterization of the potential epigenetic contribution to the spectrum of XLT and WAS is described and the implications of these findings are discussed.
authors.affiliation: Division of Pediatric Hematology, Children's Hospital Orange County, University of California at Irvine, Orange, CA, USA. dbuchbinder@choc.org
authors.forename: David
authors.initials: D
authors.lastname: Buchbinder
authors.forename: Kari
authors.initials: K
authors.lastname: Nadeau
authors.forename: Diane
authors.initials: D
authors.lastname: Nugent
mesh_terms: D058070:Asymptomatic Diseases; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D002478:Cells, Cultured; D002648:Child; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000276:immunology; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007239:Infections; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013921:Thrombocytopenia; D014430:Twins, Monozygotic / Q000235:genetics; D014923:Wiskott-Aldrich Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053632:X-Linked Combined Immunodeficiency Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*
chemical_list: D001323:Autoantibodies; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein