Female haemophiliac homozygous for the factor VIII intron 22 inversion mutation, with transcriptional inactivation of one of the factor VIII alleles.

Summary.  Phenotypic expression of X-linked recessive disorders, including haemophilia A, is rare in females. This report describes a female with sporadic severe haemophilia A. The female patient and her family members were evaluated by coagulation assays. Visible detectable disturbance of X chromosome structure or number, as well as 2N von Willebrand disease, were excluded as possible explanations of the haemophilia A phenotype. Molecular studies, factor VIII (FVIII) intron 22 inversion mutation analysis showed that the severe haemophilia A phenotype is the result of a maternally inherited, distal, FVIII gene inversion and a paternally inherited de novo, also distal, FVIII gene inversion. Furthermore, comparative single-stranded conformation polymorphism analysis revealed the absence of detectable maternally inherited abnormal FVIII gene transcript in the patient's peripheral blood lymphocytes. X chromosome methylation analysis indicates that this could be explained by preferential inactivation of the maternally inherited X chromosome carrying the distal FVIII gene inversion.