title: Severe perinatal thrombosis in double and triple heterozygous offspring of a family segregating two independent protein S mutations and a protein C mutation.
abstract: Molecular genetic and phenotypic analyses were performed in a highly unusual case of combined protein S and protein C deficiency manifesting in a family in which a child had died perinatally from renal vein thrombosis. Antenatal diagnosis in a second pregnancy was initially performed by indirect restriction fragment length polymorphism (RFLP) tracking using a neutral dimorphism within the PROS gene and served to exclude severe protein S deficiency. Am umbilical vein blood sample at 22 weeks gestation showed isolated protein C deficiency. This pregnancy proceeded to a full-term delivery without thrombotic complications. Molecular genetic analysis of the PROC and PROS gene segregating in the family then yielded one PROC gene lesion in the father and two PROS gene lesions, one in each parent. These lesions were shown to segregate with the respective deficiency states through the family pedigree. Analysis of DNA from paraffin-embedded liver tissue taken from the deceased child showed the presence of both PROS mutations, as well as the PROC mutation. Genotypic analysis of the second child showed a PROC mutation, but neither PROS mutation consistent with its possession of normal protein S levels and a low/borderline protein C level. Antenatal diagnosis was then performed in a third pregnancy by direct mutation detection. However, although the fetus carried only the paternal PROS and PROC gene lesions, the child developed renal thrombosis in utero. It may be that a further genetic lesion at a third locus still remains to be defined. Alternatively, the intrauterine development of thrombosis in this infant could have been caused, at least in part by a transplacental thrombotic stimulus arising in the protein S-deficient maternal circulation. This analysis may, therefore, serve as a warning against extrapolating too readily from genotype to phenotype in families with a complex thrombotic disorder.
authors.affiliation: Department of Biochemistry, Imperial College, London, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Formstone
authors.forename: P J
authors.initials: PJ
authors.lastname: Hallam
authors.forename: E G
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: J
authors.initials: J
authors.lastname: Voke
authors.forename: M
authors.initials: M
authors.lastname: Layton
authors.forename: K
authors.initials: K
authors.lastname: Nicolaides
authors.forename: I M
authors.initials: IM
authors.lastname: Hann
authors.forename: D N
authors.initials: DN
authors.lastname: Cooper
mesh_terms: D005260:Female; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D010375:Pedigree; D011247:Pregnancy; D011486:Protein C / Q000235:genetics*; D017293:Protein S / Q000235:genetics*; D013927:Thrombosis / Q000097:blood / Q000151:congenital / Q000235:genetics*
chemical_list: D011486:Protein C; D017293:Protein S