Genetic causes of haemophilia in women and girls

Abstract

Women and girls reported as “haemophilic females” may have complex genetic causes for their haemophilia phenotype. In addition, women and girls may have excessive bleeding requiring treatment simply because they are heterozygous for haemophilia alleles. While severe and moderate haemophilia are rare in females, 16% of patients with mild haemophilia A and almost one‐quarter of those with mild haemophilia B seen in U.S. haemophilia treatment centres are women and girls. A phenotypic female with a low level of factor VIII or factor IX may be classified into one of the following categories of causality: homozygosity (two identical haemophilia alleles), compound heterozygosity (two different haemophilia alleles), hemizygosity (one haemophilia allele and no normal allele), heterozygosity (one haemophilia allele and one normal allele), genetic causes other than haemophilia and non‐genetic causes. Studies required for classification may include coagulation parameters, F8 or F9 sequencing, F8 inversion testing, multiplex ligation‐dependent probe amplification, karyotyping and X chromosome inactivation studies performed on the patient and parents. Women and girls who are homozygous, compound heterozygous or hemizygous clearly have haemophilia, as they do not have a normal allele. Heterozygous women and girls with factor levels below the haemostatic range also meet the definitions used for haemophilia treatment.

The Clinical Genetics of Hemophilia B (Factor IX Deficiency)

“…52 Presence of other disease genes on the X chromosome has been reported to cause preferential XCI leading to HA, but no such cases have been described in HB. 12 As noted above, genetically proven heterozygotes with no overt X chromosome structural defect may have FIX levels diagnostic of HB. Eighteen of these have been studied in depth, with twelve demonstrated to have excessively skewed X-inactivation patterns, as reviewed.…”

“…Although males are affected much more often, females may have the disorder, as discussed below, and apparent female sex does not exclude the diagnosis. 12 Both HA and HB will result in prolongation of the activated partial thromboplastin time (APTT), except in the milder forms. HB is diagnosed by measurement of FIX activity in plasma using a one-stage clot-based or chromogenic substrate assay.…”

Women and girls with haemophilia receiving care at specialized haemophilia treatment centres in the United States

“…Today, it is known that women and girls can have haemophilia A (HA) or haemophilia B (HB) for a variety of genetic reasons. 1 Females require the same doses and frequencies of factor infusions as affected males with similar factor VIII activity (FVIII) or factor IX activity (FIX) levels and, similar to males, require an individualized approach depending on bleeding phenotype. The actual number of females requiring care is unknown.…”

Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses

“…Female HA carriers are typically asymptomatic because their factor VIII levels correspond to approximately half of the concentration found in healthy individuals, which is generally sufficient for normal hemostasis [8]. However, in rare cases, a carrier may exhibit symptoms of moderate to severe HA due to various reasons, including: homozygosity or compound heterozygosity for F8 gene mutations, Turner syndrome, or abnormally skewed inactivation of the normal X chromosome [9]. In a retrospective, multicenter study of females with moderate to severe hemophilia, skewed XCI accounted for the majority of cases [10].…”