Inoue Hirofumi, Terachi Shin-Ichi, Uchiumi Takeshi, Sato Tetsuji, Urata Michiyo, Ishimura Masataka, Koga Yui, Hotta Taeko, Hara Toshiro, Kang Dongchon, Ohga Shouichi
Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Division of Pediatrics, Yamaguchi Red Cross Hospital, Yamaguchi, Japan.
Pediatr Blood Cancer. 2017 Jul;64(7). doi: 10.1002/pbc.26404. Epub 2017 Jan 23.
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).
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.
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.
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).
严重蛋白C（PC）缺乏是一种罕见的遗传性易栓症，可导致新生儿期发生血栓栓塞事件。目前尚不清楚携带完整蛋白C基因（PROC）缺陷的个体如何发生或避免新生儿中风或暴发性紫癜（PF）。
我们基于我们的队列研究（n = 12）和日本之前的报告（n = 10），对22例PROC基因双突变的PC缺乏患者的发病情况和基因型进行了研究。
20个不相关家庭中的22例患者有4个纯合突变和18个复合杂合突变。16例新生儿出现PF（n = 11，69%）、颅内血栓栓塞和出血（n = 13，81%）或两者皆有（n = 8，50%），大多数患者血浆PC活性<10%。另外6例患者在15岁以后首次发生明显的血栓栓塞，血浆PC活性中位数为31%（范围：19 - 52%）。22例患者中有15例（68%）具有日本报道的5种主要突变（G423VfsX82、V339M、R211W、M406I和F181V）或另外两种突变（E68K和K193del）。6例晚发病例中有3例携带K193del突变，而16例新生儿病例中均无此突变，据报道K193del突变是中国易栓症最常见的变异型。在一个有两名晚发患者的家庭中确定了一种新的A309V突变。
就易栓症发病时间（新生儿期发病或晚发）而言，PROC双突变体的基因型多样性可能低于杂合突变体。
