Hirofumi Inoue1, Shin-Ichi Terachi2,3, Takeshi Uchiumi4, Tetsuji Sato5, Michiyo Urata4, Masataka Ishimura3, Yui Koga4, Taeko Hotta4, Toshiro Hara3, Dongchon Kang4, Shouichi Ohga1. 1. Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan. 2. Division of Pediatrics, Yamaguchi Red Cross Hospital, Yamaguchi, Japan. 3. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 4. Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan. 5. Department of Pediatrics, University of Occupational and Environmental Health, Kitakyushu, Japan.
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). PROCEDURE: 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).
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). PROCEDURE: We studied the onset of disease and the genotype of 22 PC-deficientpatients 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: Atsuki Yamashita; Yuqi Zhang; Michel F Sanner; John H Griffin; Laurent O Mosnier Journal: J Thromb Haemost Date: 2020-03-05 Impact factor: 5.824