title: von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP.
abstract: Thrombotic thrombocytopenic purpura (TTP) is caused by the persistence of the highly reactive high-molecular-weight multimers of von Willebrand factor (VWF) due to deficiency of the specific VWF-cleaving protease (VWF-CP) ADAMTS13, resulting in microangiopathic disease. The acquired form is caused by autoantibodies against VWF-CP, whereas homozygous or compound heterozygous mutations of ADAMTS13 are responsible for recessively inherited TTP. We investigated 83 children with hemolytic or thrombocytopenic episodes with or without additional neurologic symptoms or renal failure. The presumed diagnosis was chronic idiopathic thrombocytopenic purpura (ITP; n = 50), TTP (n = 8), hemolytic uremic syndrome (HUS; n = 24), and Evans syndrome (n = 1). A severe deficiency of VWF-CP (< or = 5%) was found in all investigated patients with TTP and in none of those with HUS. Additionally, 2 of 50 patients with a prior diagnosis of ITP were deficient for VWF-CP. Antibodies against VWF-CP were found in 4 children. Mutation analysis of the ADAMTS13 gene in the patients deficient in VWF-CP by direct sequencing of all 29 exons identified 8 different mutations, suggesting the hereditary form of TTP in 1 patient with ITP, in the patient with Evans syndrome, and in 5 of the 8 patients with TTP. The phenotype of TTP in childhood can be rather variable. Besides the classical clinical picture, oligosymptomatic forms may occur that can delay the identification of patients at risk.
authors.affiliation: Children's University Hospital, Hamburg-Eppendorf; Lab Association Prof Arndt and Partners, Coagulation Laboratory, Hamburg, Germany. schneppenheim@uke.uni-hamburg.de
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.forename: Ulrich
authors.initials: U
authors.lastname: Budde
authors.forename: Florian
authors.initials: F
authors.lastname: Oyen
authors.forename: Dorothea
authors.initials: D
authors.lastname: Angerhaus
authors.forename: Volker
authors.initials: V
authors.lastname: Aumann
authors.forename: Elke
authors.initials: E
authors.lastname: Drewke
authors.forename: Wolf
authors.initials: W
authors.lastname: Hassenpflug
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
authors.forename: Karim
authors.initials: K
authors.lastname: Kentouche
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kohne
authors.forename: Karin
authors.initials: K
authors.lastname: Kurnik
authors.forename: Dirk
authors.initials: D
authors.lastname: Mueller-Wiefel
authors.forename: Tobias
authors.initials: T
authors.lastname: Obser
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
mesh_terms: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D019943:Amino Acid Substitution; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006463:Hemolytic-Uremic Syndrome / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000175:diagnosis / Q000201:enzymology; D011697:Purpura, Thrombotic Thrombocytopenic / Q000151:congenital / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D013577:Syndrome
chemical_list: D001323:Autoantibodies; D018389:Codon, Nonsense; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human