Haemophilia A and B occur due to mutations in the genes encoding for factor VIII and factor IX, respectively. Both of these clotting factors form a part of the intrinsic pathway of coagulation. Hemophilia A has a prevalence of 1 in 5000 male live births, whereas that of hemophilia B is 1 in 30,000. While mild hemophilia cases exhibit excessive bleeding only after a trauma or surgery, severe hemophilia cases show frequent episodes of spontaneous or excessive bleeding, typically into joints and muscles, following minor trauma. The management of hemophilia A and B comprises many plasma-derived and recombinant forms of factor VIII and IX products, respectively.1

Hemophilia C, which is a rarer form, occurs due to the deficiency of factor XI, with an estimated prevalence of 1 case per 100,000 people in the United States.2 

Inheritance Patterns in Hemophilia A, B, and C

The inheritance pattern in hemophilia A3 and B4 is X-linked recessive, occurring due to an abnormal gene on the X chromosome. Females possess two X chromosomes, therefore those having the diseased gene on only 1 of their X chromosomes become “carriers” of this disease. They do not show any symptoms because the presence of another normal or healthy copy of the gene compensates for the copy with the disease-causing mutation.3,4

As males possess a single X chromosome, they develop disease symptoms when they inherit an X chromosome containing a disease-causing gene. In general, males with X-linked disorders pass the disease genes to all of their daughters, who become carriers if the other X chromosome from their mother is normal. A male can never pass an X-linked gene to his sons because fathers always pass their Y chromosome to male children. Female carriers of an X-linked disorder have a 25% chance in each pregnancy of having a carrier daughter, a 25% chance of having a non-carrier daughter, a 25% chance of having an affected son, and a 25% chance of having an unaffected son.3,4

Factor XI deficiency, or hemophilia C, shows an autosomal recessive pattern of inheritance. These disorders occur when an individual inherits a non-working gene from each parent. In cases of one working gene and one non-working gene, the individual becomes a carrier for the disease, but does not show symptoms. The risk for 2 carrier parents to both pass the non-working gene and, thus, have an affected child is 25% with each pregnancy. The risk of having a carrier child is 50% with each pregnancy. The chances for a child to inherit working genes from both parents is 25%. The risk is similar for males and females. In some cases, factor XI deficiency shows an autosomal dominant inheritance pattern.5

Hemophilia A

Hemophilia A occurs due to an inherited or acquired genetic mutation resulting in dysfunction or deficiency of factor VIII or an acquired inhibitor that binds to factor VIII.6

The F8 gene is situated on the X chromosome, and about 70% of cases of hemophilia A show an X-linked inheritance. The remaining 30% cases result due to de novo mutations in the absence of a family history of the disease.3

The mutation to intron 22 of the F8 gene takes place during spermatogenesis and is a main cause of severe factor VIII deficiency in around 40% of cases. Point mutations can lead to mild, moderate, or severe deficiency of factor VIII, based on the effect of that mutation on factor VIII gene function.6

Read more about hemophilia A

Missense mutations, like the G-to-A single-base substitution, lead to a dysfunctional protein in which factor VIII antigen is present with reduced factor VIII activity. These mutations also show associations with mild, moderate, or severe factor VIII reductions and with the development of factor VIII inhibitors. Gene deletions can also cause factor VIII deficiency, with large gene deletions resulting in severe hemophilia and undetectable factor VIII antigen. These individuals are also more prone to inhibitor development. Insertions are unusual in the factor VIII gene, but if present, can cause severe hemophilia A.7 Nonsense mutations and abnormal splicing can also be seen.

Female carriers, called heterozygotes, have a single copy of the gene for hemophilia A and a normal copy of the F8 gene compensating for the copy with the mutation. In cases of a female with a large proportion of the X chromosome with the normal gene inactivated, disease symptoms may develop. Based on the proportion of the X chromosome with the disease-causing copy of the gene, a female can show symptoms of mild hemophilia.3

Hemophilia B

Hemophilia B occurs due to mutations in the F9 gene, which is present at the distal end of the long arm of the X chromosome. The gene consists of 8 exons and spans 33.5 kb.8

Numerous mutations with variable amino acid substitutes have been documented in hemophilia B. These consist of missense mutations, partial and total deletions, and other mutations resulting in a reduced or lack of production of factor IX or an abnormal protein production. It is important to acquire knowledge about specific gene defects in families with severe hemophilia for the purpose of complete gene tracking, carrier analysis, and prenatal diagnosis.

Read more about hemophilia B

An unusual form of factor IX deficiency, known as hemophilia B Leyden, is seen in approximately 3% of all hemophilia B cases. Based on the presence of the particular hemophilia B Leyden mutation, minute levels of factor IX are present early in life and show an increase over a period of time. By the time patients reach middle age, factor IX levels reach the low end of normal values, and therefore treatment for bleeding episodes is no longer needed.

Hemophilia C

Mutations in the F11 gene cause factor XI deficiency, or hemophilia C. The F11 gene encodes for factor XI, which is one of the proteins required for blood clot formation. Mutations of the F11 gene cause deficient levels of functional factor XI. Patients usually have variable levels of residual factor XI. The disease severity does not always show a correlation with the residual activity of factor XI. For instance, patients with severe deficiencies of factor XI can present with mild or no symptoms, and patients with partial deficiencies can show more severe symptoms. This observation indicates that the severity of the disorder is based on additional genetic and environmental factors as well. This variability is also noted in affected family members.10

Read more about hemophilia C

In some cases, factor XI deficiency can occur in association with Noonan syndrome. This disorder shows a vast range of symptoms and physical features. The associated abnormalities include a typical facial appearance, a webbed or broad neck, a low posterior hairline, a characteristic chest deformity, and short stature. Noonan syndrome shows an autosomal dominant pattern of inheritance.

References

  1. Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis. 2012;7:24. doi:10.1186/1750-1172-7-24
  2. Gupta V. Hemophilia C, Medscape. Updated December 18, 2020. Accessed August 2, 2021.
  3. Hemophilia A. National Organization for Rare Disorders. Accessed August 2, 2021.
  4. Hemophilia B. National Organization for Rare Disorders. Accessed August 2, 2021.
  5. Factor XI deficiency. National Organization for Rare Disorders. Accessed August 2, 2021.
  6. Drelich DA. Hemophilia A. Medscape. Updated June 5, 2020. Accessed August 2, 2021.
  7. Roelse JC, De Laaf RT, Timmermans SM, Peters M, Van Mourik JA, Voorberg J. Intracellular accumulation of factor VIII induced by missense mutations Arg593–>Cys and Asn618–>Ser explains cross-reacting material-reduced haemophilia A. Br J Haematol. 2000;108(2):241-246. doi:10.1046/j.1365-2141.2000.01834.x
  8. Li T, Miller CH, Payne AB, Craig Hooper W. The CDC Hemophilia B Mutation Project mutation list: a new online resource. Mol Genet Genomic Med. 2013;1(4):238-245. doi:10.1002/mgg3.30
  9. Zaiden RA. Hemophilia B. Medscape. Updated October 2, 2020. Accessed August 2, 2021.
  10. Factor XI deficiency (hemophilia C). Canadian Hemophilia Society. Accessed August 2, 2021.

Reviewed by Kyle Habet, MD, on 8/10/2021.