Trisomy X conferring moderate hemophilia A by extremely skewed X-chromosome inactivation

Background: Hemophilia carriers occasionally present with bleeding tendency due to skewed inactivation of normal F8 carrying X chromosome.

Key clinical question: Can extreme skewing of X-chromosome inactivation (XCI) with trisomy X cause low factor (F) VIII activity and bleeding in a hemophilia carrier?.

Clinical approach: A young female with low FVIII activity (2 IU/dL), who presented with history of frequent bleeding and F8 variant, NP_000123.1:p.(Arg1800His), was identified. The mother was also confirmed genetically as hemophilia carrier. Karyotype was 47, XXX, multiplex ligation-dependent probe amplification for aneuploidy in the family identified trisomy X only in the index case. Digital polymerase chain reaction using leucocytes, urine, and oral mucosa identified one maternal F8 variant carrying and 2 wild-type F8 carrying X chromosomes, but it detected no somatic mosaicisms. Methylation-sensitive-HpaII-polymerase chain reaction assay showed predominantly activated maternal and 2 fully inactivated paternal X chromosomes. The XCI patterns using tissues of different developmental origins showed extremely skewed XCI.

Conclusion: Extreme skewing of XCI can occur even in hemophilia carriers with trisomy X, conferring frequent bleeding and low FVIII activity.