title: Novel ADAMTS13 mutations in an obstetric patient with Upshaw-Schulman syndrome.
abstract: Upshaw-Schulman syndrome (USS) is a rarely reported congenital form of thrombotic thrombocytopenic purpura (TTP) that results from mutations in the ADAMTS13 gene. Many USS patients are diagnosed during the second or third trimester of their first pregnancy. We present a patient diagnosed with USS following retinal detachments and intrauterine fetal demise at 34 weeks of gestation. The patient's plasma was tested for ADAMTS13 activity, inhibitor, and antibody. Subsequently, she and her first-degree relatives had ADAMTS13 gene sequencing. Initially, the patient was found to have an ADAMTS13 activity of <5% in the absence of an ADAMTS13 inhibitor (FRETS assay) or antibody (immunoassay). Repeat studies in the months following hospital discharge showed persistent, undetectable ADAMTS13 activity and she was given a clinical diagnosis of USS. Molecular sequencing demonstrated two novel missense mutations in the ADAMTS13 gene: one in the maternal exon 17 (p.Ala690Thr due to nucleotide substitution c.2068 G>A) and another in the paternal exon 22 (p.Arg915Cys due to nucleotide substitution c.2746 C>T). In addition to being compound heterozygous for two ADAMTS13 mutations, the patient also had two maternally inherited single nucleotide polymorphisms: p.P618A (exon 16) and p.A732V (exon 18). Her parents and only sister had normal or near-normal ADAMTS13 activity. Each was heterozygous for one of the novel missense mutations. This case highlights the importance of molecular analysis of the ADAMTS13 gene in patients and family members when the severe ADAMTS13 deficiency does not appear to be autoimmune in nature.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249, USA. tdeal@uab.edu
authors.forename: Taylor
authors.initials: T
authors.lastname: Deal
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Kremer Hovinga
authors.forename: Marisa B
authors.initials: MB
authors.lastname: Marques
authors.forename: Jill
authors.initials: J
authors.lastname: Adamski
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071120:ADAMTS13 Protein; D000328:Adult; D005260:Female; D006801:Humans; D009154:Mutation; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000235:genetics*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics*
chemical_list: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human