Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Haemophilia. 2013 May;19(3):378-84. doi: 10.1111/hae.12097. Epub 2013 Feb 4.
Severe heritable protein C (PC) deficiency is quite rare, although heterozygous PROC mutation is the second leading cause of genetic predisposition to thrombosis in Japanese adults. The aim of the study was to search the optimal management, the paediatric onset and outcomes of PC deficiency were characterized in Japan. The genetic study, postmarketing survey of activated PC(aPC) concentrate (Anact(®)C) and intensive review in Japan for 20 years enabled the analysis of the disease onset, genotype, treatment and prognosis. Symptomatic PC deficiency was determined in 27 Japanese children. All but two patients presented within 16 days after birth (three prenatal and six neonatal onsets). Postnatal-onset cases had normal growth at full-term delivery. Of the 27 patients, 19 suffered intracranial thrombosis or haemorrhage (ICTH) (three foetal hydrocephalies), 16 developed purpura fulminans (PF) and 10 had both at the first presentation. ICTH preceded PF in both affected cases. Low PC activities of 18 mothers and/or 12 fathers indicated 20 inherited PC deficiencies (2 homozygotes, 11 compound heterozygotes and 7 heterozygotes) and seven unidentified causes of PC deficiency. Nine of 11 patients studied had PROC mutations. Four unrelated patients (50%) carried PC nagoya (1362delG). No PC-deficient parents had experienced thromboembolism. Of the 18 patients with aPC therapy, two died and eight evaluable survivors had neurological sequelae. This first comprehensive study of paediatric PC deficiency suggested that perinatal ICTH was the major presentation, occurring earlier than neonatal PF. PC nagoya was prevalent in paediatric, but not adult, patients in Japan. Early maternal screening and optimal PC therapy are required for newborns at risk of PC deficiency.
严重遗传性蛋白 C (PC) 缺乏症较为罕见，尽管杂合 PROC 突变是导致日本成年人遗传易栓倾向的第二大原因。本研究旨在寻找最佳的治疗方法，描述日本儿童发病特点、结局。通过对 20 年来日本的 PC 缺乏症患者的基因研究、上市后激活 PC(aPC)浓缩物（Anact(®)C）的调查和深入回顾，分析了疾病的发病、基因型、治疗和预后。27 例日本儿童被确诊为症状性 PC 缺乏症。除两例外，所有患者均在出生后 16 天内发病（3 例产前，6 例新生儿发病）。足月儿出生后无生长迟缓。27 例患儿中，19 例颅内血栓形成或出血（ICTH）（3 例胎儿脑积水），16 例暴发性紫癜（PF），10 例首次就诊时两者兼有。两例均为 ICTH 先于 PF。18 位母亲和/或 12 位父亲的 PC 活性低提示 20 例遗传性 PC 缺乏症（2 例纯合子，11 例复合杂合子，7 例杂合子）和 7 例不明原因的 PC 缺乏症。11 例患者中有 9 例研究了 PROC 突变。4 例无血缘关系的患者（50%）携带 PC nagoya（1362delG）。无 PC 缺乏症的父母有过血栓栓塞史。18 例接受 aPC 治疗的患者中，2 例死亡，8 例可评估的存活者有神经后遗症。这是首例对日本儿童 PC 缺乏症的全面研究，提示围生期 ICTH 是主要表现，早于新生儿 PF。PC nagoya 在日本儿科患者中较为常见，但在成年患者中不常见。对于有 PC 缺乏风险的新生儿，需要进行早期的母婴筛查和优化的 PC 治疗。
