title: The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene.
abstract: BACKGROUND
  Severe protein C (PC) deficiency is a rare heritable thrombophilia leading to thromboembolic events during the neonatal period. It remains unclear how individuals with complete PC gene (PROC) defects develop or escape neonatal stroke or purpura fulminans (PF).
  
  
  METHODS
  We studied the onset of disease and the genotype of 22 PC-deficient patients with double mutations in PROC based on our cohort (n = 12) and the previous reports (n = 10) in Japan.
  
  
  RESULTS
  Twenty-two patients in 20 unrelated families had 4 homozygous and 18 compound heterozygous mutations. Sixteen newborns presented with PF (n = 11, 69%), intracranial thromboembolism and hemorrhage (n = 13, 81%), or both (n = 8, 50%), with most showing a plasma PC activity of <10%. Six others first developed overt thromboembolism when they were over 15 years of age, showing a median PC activity of 31% (range: 19-52%). Fifteen of the 22 patients (68%) had the five major mutations (G423VfsX82, V339M, R211W, M406I, and F181V) or two others (E68K and K193del) that have been reported in Japan. Three of the six late-onset cases, but none of the 16 neonatal cases, had the K193del mutation, which has been reported to be the most common variant of Chinese thrombophilia. A novel mutation of A309V was determined in a family of two patients with late onset.
  
  
  CONCLUSIONS
  The genotype of double-PROC mutants might show less diversity than heterozygous mutants in terms of the timing of the onset of thrombophilia (newborn onset or late onset).
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Division of Pediatrics, Yamaguchi Red Cross Hospital, Yamaguchi, Japan.|Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Terachi
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.affiliation: Department of Pediatrics, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Urata
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Ishimura
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Hotta
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Dongchon
authors.initials: D
authors.lastname: Kang
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011486:Protein C / Q000235:genetics*; D020151:Protein C Deficiency / Q000235:genetics*; D055815:Young Adult
chemical_list: D011486:Protein C
keywords: compound heterozygous mutation; pediatric stroke; pediatric thrombophilia; protein C deficiency; purpura fulminans