Intracerebral mass bleeding in a term neonate: Manifestation of hereditary Protein S deficiency with a new mutation in the PROS1 Gene

Background: Vitamin K deficiency, birth asphyxia, birth trauma and malformation of blood vessels are the major causes for intracranial bleeding in term neonates and are therefore considered first line in any term neonate with severe haemorrhage. In contrast, the most common manifestation of hereditary prothrombotic disorders during the neonatal period is thrombosis of A. cerebri media or sinus thrombosis. However, the rate of unexplained cases of term newborns with intracerebral mass bleeding remains up to 25%. Case: A primarily healthy male term newborn was admitted to the neonatal intensive care unit on the fourth day of life with seizures and haemorrhagic shock. The laboratory data showed a severe anemia and consumption of platelets and coagulation factors. Vitamin K deficiency dependent bleeding could be excluded because of normal age-related activity of vitamin K dependent protein C. (Hb 9.0mg/dl, HCT 23%, PLT 10/nl, TPZ and aPTT: not measurable, fibrinogen 47mg/dl, antithrombin 74%, d-dimers 6900/µl, protein C activity 47%). Cerebral ultrasound revealed left sided intraparenchymatous bleeding as bleeding origin. MRI findings supported a subarachnoideal and diffuse intracerebral mass bleeding. Vitamin K deficiency related bleeding and other hereditary haemophiliac diseases were excluded in the following diagnostic work up. However, a hereditary prothrombotic disorder, a homozygous protein S deficiency with a new mutation in the protein S (PROS1) gene (c.701A>G, p.Tyr234Cys) was found. The patient experienced an additional thrombosis of A. abdominalis and expired on the 8^th day of life. Conclusion: Congenital prothrombotic disorders have to be considered in the differenzial diagnosis of severe neonatal intracranial haemorrhage. This newly described mutation in the PROS1 gene (c.701A>G, p.Tyr234Cys) appears to have highly clinical relevance.