Haemophilia in European royalty

Haemophilia figured prominently in the history of European royalty in the 19th and 20th centuries. Queen Victoria and her husband, Prince Albert, of the United Kingdom, through two of their five daughters – Princess Alice and Princess Beatrice – passed the mutation to various royal houses across the continent, including the royal families of Spain, Germany, and Russia. Victoria's youngest son, Prince Leopold, Duke of Albany, also had the disease, though none of her three elder sons did. Tests on the remains of the Romanov imperial family show that the specific form of haemophilia passed down by Queen Victoria was probably the relatively rare haemophilia B.^[1] The presence of haemophilia B within the European royal families was well-known, with the condition once popularly known as "the royal disease".

The sex-linked X chromosome bleeding disorder manifests almost exclusively in males, even though the genetic mutation causing the disorder is located on the X chromosome and can be inherited from the mother by male children or from either mother or father by female children. This is because the trait is recessive, meaning that only one correctly functioning copy of the blood clotting factor gene is necessary for normal clotting. Females have two X chromosomes, and hence redundant copies of the blood clotting factor gene located on them. A female who inherits a mutated copy on one X chromosome has also inherited a second X chromosome from the other parent that is likely to carry a non-mutated copy of the gene, capable of directing appropriate clotting. Such a female, with normal clotting but possessing a single mutated copy of the gene, is called a carrier. Males possess only a single X chromosome, inherited from their mother, having received a Y chromosome from their fathers instead of a second X. If their sole X chromosome contains the haemophilia mutation they possess no second copy to provide for normal function, as in carrier females. Each child of a carrier will have a 50% chance of inheriting their mother's mutation, of being a haemophiliac (sons) or carrier (daughters). The daughter of a male haemophiliac will always inherit his mutation, while a son cannot ever inherit it. A female will be affected with haemophilia only in the rare circumstance that she inherits mutated X chromosomes from both a haemophiliac father and a carrier or a haemophiliac mother. No case of such double inheritance is known among Queen Victoria's descendants.

Although an individual's haemophilia can usually be traced in the ancestry, in about 30% of cases there is no family history of the disorder, and the condition is speculated to be the result of spontaneous mutation in an ancestor.^[2] Victoria's appears to have been a spontaneous or de novo mutation, most likely inherited from one of her parents, and she is usually considered the source of the disease in modern cases of haemophilia among her descendants. Queen Victoria's mother, Victoria, Duchess of Kent, was not known to have a family history of the disease, although it is possible that she was a carrier, but among her three children only Victoria received the mutated copy. Queen Victoria's father, Prince Edward, Duke of Kent, was not a haemophiliac, but the mutation may have arisen as a germline mutation within him. The rate of spontaneous mutation is known to increase with paternal age (and is higher in fathers than in mothers at all ages); Victoria's father was 51 at her birth. The probability of Victoria's mother having had a lover with haemophilia is minuscule given the low life expectancy of early 19th-century haemophiliacs.

Queen Victoria's eldest daughter, Victoria, Princess Royal, apparently escaped the haemophilia gene, as it did not appear in any of her matrilineal descendants. Victoria's fifth child, Princess Helena, may or may not have been a carrier; two healthy sons survived to adulthood, but one son died in infancy, another was stillborn, and her two daughters did not have issue. Victoria's sixth child, Princess Louise, died without issue. Queen Victoria's sons Edward VII, Alfred, Duke of Saxe-Coburg and Gotha, and Prince Arthur, Duke of Connaught and Strathearn were not haemophiliacs; however, her daughters Alice and Beatrice were confirmed carriers of the gene, and Victoria's son Leopold had haemophilia, making his daughter Princess Alice, Countess of Athlone a carrier as well.