Thrombophilia Due To Protein C Deficiency, Autosomal Recessive
A number sign (#) is used with this entry because autosomal recessive hereditary thrombophilia due to protein C deficiency is caused by homozygous or compound heterozygous mutation in the PROC gene (612283) on chromosome 2q14.
See also autosomal dominant thrombophilia due to protein C deficiency (THPH3; 176860), an allelic disorder caused by heterozygous mutation in the PROC gene.Description
Autosomal recessive protein C deficiency resulting from homozygous or compound heterozygous PROC mutations is a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia (Millar et al., 2000).Clinical Features
Branson et al. (1983) reported a newborn male infant with intractable purpura fulminans, which reflected massive subcutaneous thrombosis. His mother had heterozygous protein C deficiency. This was the first instance in which protein C deficiency was implicated in disseminated intravascular coagulation (DIC).
Seligsohn et al. (1984) studied an Arab-Israeli family in which 2 sibs with first-cousin parents died with massive venous thrombosis in the neonatal period. Both parents and several other relatives, who were heterozygous carriers, had had no thrombotic episodes.
Marlar (1985) diagnosed complete deficiency of protein C in 5 infants. The major symptom was massive subcutaneous thrombosis that usually started within the first 24 hours of life.
Peters et al. (1988) described a patient with neonatal purpura fulminans and severe bilateral vitreous hemorrhages. The patient showed reduced protein C antigen levels with undetectable activity levels. Infusions of fresh frozen plasma were given for 8 months.
Gruppo et al. (1988) reported a child who had renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. Protein C levels and anticoagulant activity were decreased to 47% and 14% of normal, respectively. A 3-year-old asymptomatic sib had a similar reduction of PROC anticoagulant activity. The mother had type I protein C deficiency with a proportionate reduction in immunologic protein levels (59%) and anticoagulant activity (52%), whereas the father had type II PROCC deficiency with normal immunologic protein levels (102%), and low anticoagulant function (50%). Electrophoretic studies showed an abnormal protein C in the father and both children. Gruppo et al. (1988) concluded that the children were compound heterozygous for the 2 different types of PROC deficiency inherited from each of the parents.
Tuddenham et al. (1989) reported a consanguineous family in which 2 members had homozygous protein C deficiency. Both presented in the second half of their first year of life with recurrent rapidly disappearing ecchymotic skin lesions, DIC, and venous thrombosis. The authors noted that homozygous deficiency usually presents in the neonatal period. Successful treatment was achieved by frequent infusions of plasma or prothrombin complex with warfarin maintenance.
Dreyfus et al. (1991) stated that at least 19 cases of life-threatening neonatal thrombosis and purpura fulminans had been described.
Fong et al. (2010) reported 2 sisters with autosomal recessive protein C deficiency who had extensive bilateral periventricular hemorrhagic infarction causing spastic cerebral palsy. The older sister presented at 20 months with cortical visual blindness, spastic diplegia, and purpura fulminans. The younger sister presented at age 3 days with apneas and multifocal seizures. At age 2 years, she had global developmental delay, cortical visual blindness, spastic quadriplegia, epilepsy, and purpura fulminans. Neuroimaging of both sibs showed findings consistent with bilateral cerebral intramedullary venous thrombosis occurring at under 28 weeks' gestation for the older sister and around time of birth for the younger sister. Laboratory studies showed severe qualitative reduction in plasma protein C anticoagulant activity.
Melissari and Kakkar (1989) reported 2 unrelated families in which 4 adults had severe protein C deficiency with less than or equal to 5% of normal plasma levels. Newborn deaths were reported in the first family but not in the second family. Adult patients developed thrombotic symptoms mainly in their early twenties, characterized by recurrent superficial and deep iliofemoral vein thromboses and pulmonary emboli. Other clinical features included generalized peritonitis due to massive mesenteric vein thrombosis, thrombosis of the cavernous sinus, renal vein thrombosis, and priapism. In the second family, 5 individuals died of intravascular abdominal thrombosis at about 40 years of age. Massive thromboembolic episodes were associated with a compensated DIC syndrome. Clinical symptoms could be controlled by long-term administration of low molecular weight heparin alone or in combination with low dose warfarin.
Tripodi et al. (1990) reported a family in which 2 protein C deficiency homozygotes with similarly low protein C levels had mild disease. One had recurrent venous thrombosis starting at the age of 28 years, and the other was still asymptomatic at 38 years despite exposure to thrombotic risk factors. A review of 13 additional homozygotes revealed a highly variable phenotypic expression, which the authors subdivided into 2 groups. In the first group, affected homozygotes from 8 kindreds presented at birth with unmeasurable protein C levels and life-threatening thrombosis, whereas affected homozygous individuals of 1 kindred had very low levels of protein C and delayed onset of thrombosis at about 10 months of age. In a second group of 4 kindreds, homozygotes had very low, but measurable, protein C levels and survived into adulthood with histories of moderately severe thrombosis. Tripodi et al. (1990) noted that the findings in their family demonstrated that protein C levels lower than 10% are compatible with a negative history for thrombosis, not only in the neonatal period but also during adulthood. These results suggested that other factors need to interact for full clinical penetrance of the defect in some homozygotes.Clinical Management
Marlar (1985) noted that treatment of affected infants with heparin, antiplatelet drugs, or both, was not effective. The only successful treatment was protein C replacement using fresh frozen plasma or factor IX concentrate.
In a newborn Chinese boy with homozygous protein C deficiency, Dreyfus et al. (1991) found that long-term therapy with concentrated protein C was well tolerated.
Muller et al. (1996) described the successful use of protein C concentrate in a homozygous protein C-deficient infant for 8 months until oral anticoagulation was initiated. The availability of a protein C concentrate purified by monoclonal antibody allowed specific replacement of protein C, thus avoiding problems of fluid overload from use of fresh frozen plasma. An occlusive-hydrocolloid bandage was effective in local treatment of skin lesions.
Angelis et al. (2001) reported en bloc heterotopic auxiliary liver and bilateral renal transplantation in a patient with homozygous protein C deficiency.Molecular Genetics
Among 9 unrelated patients with severe autosomal recessive protein C deficiency, Millar et al. (2000) identified 13 different biallelic mutations, including 8 novel mutations (see, e.g., 612283.0004) in the PROC gene.Genotype/Phenotype Correlations
Millar et al. (2000) found that plasma protein C activity levels ranged from 1 to 8% among 9 patients with severe recessive protein C deficiency, but there was not a clear correlation between residual enzyme activity and clinical thrombosis. Several patients with 0 to 1% protein activity had neonatal purpura fulminans, but 1 patient with 1% activity did not have a thrombotic episode until age 11. Conversely, a patient with 8% activity developed neonatal symptoms. However, the patient with 8% activity was also found to be homozygous for the factor V Leiden (612309.0001) mutation, which likely influenced the severity of the clinical phenotype. Another patient with 1% protein C activity and heterozygosity for the factor V Leiden mutation had a severe fatal neonatal course.