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Editor,—Homozygous protein C deficiency is rare with an estimated incidence of one in 500 000 to one in 750 000.1 It presents shortly after birth with life threatening thromboses involving the central nervous system, eyes, kidneys, and skin (purpura fulminans).2 Protein C activity, in affected individuals, is usually less than 1% (normal 70–140%).3 Management, in the acute phase, is with intravenous protein C concentrate (ImmunoAG, Vienna, Austria).4 Untreated cases usually result in death.
We present a family exhibiting a spectrum of features caused by protein C deficiency.
The pedigree is shown in Figure 1. Individuals IV:1 and IV:2 (the parents in our family) are second cousins and both heterozygous for protein C deficiency. Protein C activity is approximately 50% in both and they are healthy. The mother (IV:1) had five miscarriages and one neonatal death; the baby had undetectable protein C levels and died at the age of 4 weeks from severe purpura fulminans and cerebral involvement. Two of her children (V:3 and V:7) were healthy with normal protein C levels. One sibling (V:5) has been described previously.5 Briefly, she presented 6 days after birth with purpura fulminans on her left calf, bilateral central retinal vein occlusions, vitreous haemorrhages, and a right central retinal artery occlusion. Despite treatment with intravenous protein C concentrate she developed bilateral retinal detachments. Now, aged 7, she is bilaterally blind, has a scar corresponding to the area of purpura fulminans, but has otherwise developed normally. She receives subcutaneous protein C injections every fourth day.
The youngest child (V:10) was prenatally diagnosed as homozygous protein C deficient. She was born by emergency caesarean section at 36 weeks' gestation because of reduced fetal movements. At birth ultrasonography diagnosed an intraventricular and right intracerebral haemorrhage. Ocular examination demonstrated right leucocoria with an underlying total retinal detachment and a left macular haemorrhage. Intravenous protein C therapy (80 IU/kg) was initiated at birth and titrated relative to serum levels. Despite early intervention she developed hydrocephalus requiring a V-P shunt at 3 weeks of age. Fortunately, the left macular haemorrhage resolved leaving a relatively healthy posterior pole (Fig 2). At 3 months of age she is progressing well and showing signs of visual attention.
The clinical signs of homozygous protein C deficiency manifest from 2 hours to 2 weeks after birth.2 Ocular features associated with this condition include vitreous, retinal and subretinal haemorrhage, retinal venous and arterial occlusion, microphthalmos, and leucocoria secondary to retinal detachment or persistent hyperplastic primary vitreous.2 One or both eyes may be affected. Drefus et al reported blindness in 6/9 affected children.6 It is possible that early treatment might result in a better visual prognosis.
This family demonstrates a spectrum of clinical manifestations ranging from no symptoms in the heterozygous state to spontaneous abortion and neonatal death in the homozygous state. Individual V:10 was delivered by emergency caesarean section and a suspected intrauterine cerebral event was confirmed. This challenges the hypothesis by Hattenbachet al that thrombotic events only occur postnatally.2 In utero treatment is not currently possible because maternal supplements do not cross the placenta and the biological half life of protein C is short (<8 hours) so that direct fetal replacement is not practical.
In this family, the disease allele appears to be preferentially transmitted making accurate genetic counselling more difficult. Prenatal diagnosis is currently available and we would suggest that affected individuals are monitored closely in the final trimester of pregnancy. We have shown that in utero thrombotic events can occur around 36 weeks' gestation. This raises the question as to whether elective caesarean section should be considered at 34–36 weeks for homozygously affected individuals so that replacement protein C therapy can be given and avoid the complications associated with the deficiency.