Paediatric presentation and outcome of congenital protein C deficiency in Japan

Summary. Severe heritable protein C (PC) deficiency isquite rare, although heterozygous PROC mutation is thesecond leading cause of genetic predisposition tothrombosis in Japanese adults. The aim of the study wasto search the optimal management, the paediatric onsetand outcomes of PC deficiency were characterized inJapan. The genetic study, postmarketing survey ofactivated PC (aPC) concentrate (Anact C) and intensivereview in Japan for 20 years enabled the analysis of thedisease onset, genotype, treatment and prognosis.Symptomatic PC deficiency was determined in 27Japanese children. All but two patients presented within16 days after birth (three prenatal and six neonatalonsets). Postnatal-onset cases had normal growth at full-term delivery. Of the 27 patients, 19 suffered intracranialthrombosis or haemorrhage (ICTH) (three foetalhydrocephalies), 16 developed purpura fulminans (PF)and 10 had both at the first presentation. ICTH precededPF in both affected cases. Low PC activities of 18mothers and/or 12 fathers indicated 20 inherited PCdeficiencies (2 homozygotes, 11 compound heterozygotesand 7 heterozygotes) and seven unidentified causes of PCdeficiency. Nine of 11 patients studied had PROCmutations. Four unrelated patients (50%) carried PCnagoya (1362delG). No PC-deficient parents hadexperienced thromboembolism. Of the 18 patients withaPC therapy, two died and eight evaluable survivors hadneurological sequelae. This first comprehensive study ofpaediatric PC deficiency suggested that perinatal ICTHwas the major presentation, occurring earlier thanneonatal PF. PC nagoya was prevalent in paediatric, butnot adult, patients in Japan. Early maternal screening andoptimal PC therapy are required for newborns at risk ofPC deficiency.Keywords: activated protein C therapy, intracranialthrombosis/haemorrhage, protein C deficiency, purpurafulminans