Paediatric presentation and outcome of congenital protein C deficiency in Japan

Abstract

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.

Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency

“…However, biallelic PROC mutations are found only in half of the neonatal cases [3]. This is the first report of fetal ventriculomegaly associated with heterozygous PROC mutation.…”

“…Pediatric thrombosis occurs at the highest incidence in the newborns. The neonatal onset of the natural anticoagulant factor defects is exclusively PC-deficiency [3]. Purpura fulminans and intracranial thromboembolism are the first presentation of severe PC-deficiency.…”

“…Purpura fulminans and intracranial thromboembolism are the first presentation of severe PC-deficiency. Congenital hydrocephalus was reported in patients with homozygous or compound heterozygous PROC mutations of parental origin [3,4]. However, there is no information about the prenatal onset of heterozygous carriers.…”

Protein C deficiency as the major cause of thrombophilias in childhood

“…19 Between 1985 and 2010, this study determined 27 Japanese patients with congenital PC deficiency in Japan. These included one pair of twins, and a pair of cousins.…”

Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism

“…On the other hand, the number of patients who carried either PROC or PROS1 mutation was the same eight. The first nationwide survey for pediatric thrombophilia in Japan suggested a higher prevalence of PC deficiency than expected (24,25). The discrepancy may be explained by the wider range of PC activity than that of PS or AT activity in infant and children (18,26), partly arising from the inherent variation of PC pathway (27,28).…”