Peculiar laboratory phenotype/ genotype relationship due to compound inherited protein C defects in a child with severe venous thromboembolism

Summary

A 7-years-old child who developed unprovoked deep vein thrombosis (DVT) and pulmonary embolism (PE) was tested for inherited thrombophilia. Protein C (PC) antigen level (87 %) and PC coagulometric and amidolytic activities (12 % and 11 %, respectively) were consistent with a homozygous PC type IIA phenotype.

The patient was carrier of two heterozygous missense mutations causing p.Arg32Cys substitution associated with a type I PC defect (“null allele”, from the paternal side) and p.Gly433Ser substitution responsible for a type IIA PC defect (from the maternal side). Thus, the apparently normal PC antigen level in the proband was misleading in the interpretation of phenotype/genotype relationship of this compound PC defect. The child was also carrier of heterozygous prothrombin G20210A variant.

Severe venous thromboembolism can occur in otherwise healthy children with complex inherited thrombophilia. Careful laboratory characterization of the phenotype/genotype relationship can be crucial to correctly classify PC defects and for their management with anticoagulants or replacement therapy.

Zusammenfassung

Ein 7-jähriges Kind wurde aufgrund einer unprovozierten tiefen Venenthrombose (TVT) und Lungenembolie (LE) auf hereditäre Thrombophilien getestet. Der Antigen-Spiegel an Protein C (PC) (87 %), sowie Aktivität von PC, welche mittels koagulometrischen und chromogenem (amidolytischem) Assay bestimmt wurde (12 % bzw. 11 %), waren mit einem homozygoten PC Typ IIA Phänotyp vereinbar.

Tatsächlich war der Patient compound heterozygot, d. h. Träger von zwei unterschiedlichen Missense-Mutationen des PC-Gens: eine p.Arg32Cys Substitution, dass mit einer type I PC Defekt (“null Allel”, von der väterlichen Seite) assoziiert ist, und eine p.Gly433Ser Substitution, dass für einer type II PC defekt (von der mütterlichen Seite) verantwortlich ist.

Dies führte zu einem irreführend normalen PC Antigen Spiegel bei dem Probanden im Rahmen der Interpretation der Phänotyp/Genotyp- Beziehung dieses kombinierten PC Defekts. Das Kind war zudem heterozygoter Träger der Prothrombin G20210A Mutation.

Schwere venöse Thromboembolien können bei ansonsten gesunden Kindern mit komplex vererbten Thrombophilien auftreten. Eine sorgfältige Laborcharakterisierung der Phänotyp-/ Genotyp-Beziehung kann entscheidend sein für die korrekte Klassifizierung von PC-Defekten sowie für das Management mit Antikoagulantien oder Ersatztherapie.

Keywords

Protein C defects - children - thrombosis - thrombophilia - phenotype/genotype relationship

Schlüsselwörter

Protein C defekten - Kinder - Thrombosis - Thrombophilie - Phänotyp-/Genotyp-Beziehung

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