Hemophilia is a rare, inherited bleeding disorder characterized by the blood’s inability to clot properly, leading to prolonged and excessive bleeding after injury or surgery, and sometimes spontaneously. This condition stems from a deficiency or defect in specific proteins known as coagulation factors, which are necessary for forming a blood clot. While hemophilia is typically passed down through generations, about one-third of cases arise from a spontaneous, non-inherited gene change. Understanding the specific inheritance pattern is key to grasping why the disorder presents differently across biological sexes.
The X-Linked Recessive Inheritance Pattern
Hemophilia A and B are categorized as X-linked recessive disorders because the genes responsible for the condition are located on the X chromosome. Humans have 23 pairs of chromosomes, including the sex chromosomes: females typically have two X chromosomes (XX), and males have one X and one Y chromosome (XY). The genes containing instructions for the necessary clotting factors are found exclusively on the X chromosome.
The term “recessive” means that a person must have the genetic mutation to express the trait. In females (XX), the presence of one normal copy is usually enough to prevent the disorder. This differs from autosomal inheritance, where the mutation is found on one of the 22 non-sex chromosomes. Since males (XY) only have one X chromosome and the Y chromosome does not carry the corresponding gene, they only have one copy of the clotting factor gene.
Carrier Status and Sex Differences in Presentation
The X-linked recessive nature of hemophilia leads to a stark difference in how the condition affects males and females. Males are much more commonly affected because they possess only a single X chromosome (hemizygous). If this sole X chromosome carries the altered gene, the male will express the disorder, as there is no second functional copy to compensate for the defect.
Females, having two X chromosomes, are typically protected from developing severe hemophilia if they inherit one mutated gene and one normal gene. These females are considered carriers, able to pass the gene to their children without being severely affected themselves. However, some carrier females experience mild to moderate bleeding symptoms, such as heavy menstrual bleeding or easy bruising, often due to skewed X-inactivation. In rare instances, a female can be severely affected if she inherits two mutated genes or if her normal X chromosome is inactivated.
Predicting Inheritance Patterns in Families
Genetic counseling involves calculating the probability of hemophilia transmission through generations. In the most common scenario, a carrier mother has a child with an unaffected father. In this case, each son has a 50% chance of inheriting the affected X chromosome and having hemophilia. Each daughter has a 50% chance of becoming a carrier like her mother.
A man who has hemophilia will always pass his affected X chromosome to his daughters, making all of them obligate carriers, even if the mother is unaffected. Since a father passes the Y chromosome to his sons, he cannot pass the X-linked hemophilia gene to them, meaning none of his sons will be affected. Understanding these probabilities allows families to anticipate the risk of having an affected child or a carrier daughter.
Distinguishing Hemophilia A and Hemophilia B
While both are X-linked recessive bleeding disorders, hemophilia includes two main types: Hemophilia A and Hemophilia B. The distinction lies in the specific coagulation factor that is deficient or defective. Hemophilia A, the more common type, results from a deficiency of clotting Factor VIII, encoded by the F8 gene.
Hemophilia B, sometimes called Christmas disease, is caused by a deficiency of clotting Factor IX, encoded by the F9 gene. Both the F8 and F9 genes are located on the X chromosome. Though less common, Hemophilia B is generally considered less clinically severe than Hemophilia A. There is also a third, much rarer form, Hemophilia C (Factor XI deficiency), which is inherited differently as an autosomal disorder.