PB0988 - Homozygous Protein S Deficiency in Siblings

Background: Protein S is a glycoprotein that plays an important role in regulating thrombin generation. Congenital deficiency of protein S is an autosomal dominant disorder caused by variants in the PROS1 gene, increasing affected individuals’ risk of venous thromboembolism (VTE). Thrombosis is observed in both heterozygous and homozygous state, with mild protein S deficiency (heterozygous) most prevalent. Occurrence of compound heterozygosity or even homozygosity is considered to be extremely rare with prevalence unknown.

Aims: We present the first two cases of homozygosity for protein S deficiency, variant c.470-2A>T in African American siblings.

Methods: Retrospective review of electronic medical record of two living young adult African American siblings diagnosed with severe protein S deficiency during infancy.

Results: Two African American siblings, female age 26 and male age 25, diagnosed with homozygous protein S deficiency with baseline functional levels ranging between 4-7%. The female was diagnosed shortly following birth with typical presentation of purpura fulminans. Male sibling was diagnosed at birth given positive family history. Both have a history of retinal infarction during infancy resulting in blindness, as well as developmental delay, and language deficit. The female has a history of neonatal cerebral venous sinus thrombosis resulting in intracranial hemorrhage and seizure. The male patient has history of necrotizing enterocolitis possibly secondary to aortic embolism. Parents are heterozygous for protein S deficiency without history of VTE. Genetic testing for both siblings revealed homozygosity for PROS1 c.470-2A>T pathogenic variant. Patients remain on weekly plasma infusions and anticoagulation since birth.

Conclusion(s): Homozygosity for protein S deficiency is extremely rare, with identified variant in our patients not previously reported. This variant is not present in population databases; however, algorithms suggest that this variant may disrupt the consensus splice site leading to an absent or disrupted protein. For this reason, this variant has been classified as pathogenic.