A Rare Case of Severe Hemophilia B in Female Twins: Diagnostic and Genetic Insights

초록

Background: Hemophilia B is an X-chromosome-linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX activity (FIX:C) levels may also experience some bleeding. However, severe hemophilia B is extremely rare in females and only a few cases have been reported. Patients and Methods: we describe a case of twin girls diagnosed with severe hemophilia B but with a normal 46, XX karyotype. The diagnosis was confirmed by clinical manifestations, factor IX activities, and mutation analysis including PCR and Sanger sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), and targeted next generation sequencing (NGS). Results: Both had profoundly decreased factor IX activities (<1%) without inhibitory factor IX antibody. Their parents were non-consanguineous and had no known family history of bleeding disorders, and none of them have a bleeding tendency with normal factor IX activities (>100%). Mutation analysis revealed a de novo heterozygous nonsense mutation, c.880C>T in exon 8 of the F9 gene (p.Arg294), which was confirmed by NGS. A family study using targeted mutation analysis did not detect the mutation in either parent. Conclusion: This case highlights the rare occurrence of severe hemophilia B in a female patient, caused by a de novo heterozygous nonsense mutation in the F9 gene. It underscores the importance of considering hemophilia in symptomatic females and the utility of comprehensive genetic testing, including NGS and family studies, in confirming diagnosis and understanding inheritance patterns.