Haemophilia in European royalty

Haemophilia figured prominently in the history of European royalty in the 19th and 20th centuries. Britain's Queen Victoria, through two of her 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 son Prince Leopold, Duke of Albany suffered from the disease. For this reason, haemophilia was once popularly called "the royal disease". Tests of 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 sex-linked X chromosome disorder manifests almost entirely in males, although the gene for the disorder is located on the X chromosome and may be inherited from the mother for male children or from either mother or father for female children. Expression of the disorder is much more common in males than in females. This is because, although the trait is recessive, males only inherit one X chromosome, from their mothers. Thus if the haemophilia gene is transmitted on it, there is no possibility for the male to inherit a haemophilia-free gene from his father to mask or dilute the symptoms. By contrast, a female who inherits a gene for haemophilia on one of her X chromosomes will also have inherited a second X chromosome from the other parent which is likely to carry a haemophilia-free gene that would prevent full expression of symptoms.

Females who inherit the gene for Haemophilia A or B from both parents would be expected to manifest full symptoms, similar to those seen in affected males, but this is extremely rare. Despite frequent inter-marriage among royalty, no case of such double inheritance is known among Queen Victoria's descendants. This is largely because only one of the individuals with Hemophaelia had any children.

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 appears to have been a spontaneous or de novo mutation and is usually considered the source of the disease in modern cases of haemophilia among royalty. Queen Victoria's father, Prince Edward, Duke of Kent, was not a haemophiliac, and the probability of her mother having had a lover who suffered from haemophilia is minuscule given the low life expectancy of 19th-century haemophiliacs. Her mother, Victoria, Duchess of Kent, was not known to have a family history of the disease, although it is possible that the mutation began at her conception and was passed down only to Victoria and not to her two other children. In the same way, had Queen Victoria herself only had seven children, the mutation would probably be assumed today to have occurred at the conception of Princess Alice, as she was the only known carrier among Victoria and Albert's first seven children.

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, Helena, may or may not have been a carrier; two healthy sons survived to adulthood but two other sons died in infancy and her two daughters did not have issue. Victoria's sixth child, Louise, died without issue. Her sons Edward, Alfred, and Arthur were not haemophiliacs. However, her daughters Alice and Beatrice were confirmed carriers of the gene, and her son Leopold was a sufferer of haemophilia, making his daughter Princess Alice, Countess of Athlone a carrier as well.

Queen Victoria family tree

Princess Alice

Alice (1843-1878), Victoria's third child, and wife of the future Grand Duke Louis IV of Hesse and by Rhine (1837-1892), passed it on to at least three of her children: Irene, Friedrich, and Alix.

• Princess Victoria of Hesse and by Rhine (1863-1950), later Marchioness of Milford Haven, wife of Prince Louis of Battenberg (1854-1921) and maternal grandmother to Prince Philip, Duke of Edinburgh, apparently was not a carrier.
• Princess Elizabeth of Hesse and by Rhine (1864-1918), later Grand Duchess Elizabeth Feodorovna of Russia through her marriage to Grand Duke Sergei Alexandrovich (1857-1905), may or may not have been a carrier. Following her husband's assassination, she became a nun and was childless when killed by the Bolsheviks in 1918.
• Princess Irene of Hesse and by Rhine (1866-1953), later Princess Heinrich of Prussia, through her marriage to Prince Heinrich of Prussia (1862-1929), passed it on to two of her three sons:
  • Prince Waldemar of Prussia (1889-1945). Survived to age 56; had no issue.
  • Prince Heinrich of Prussia (1900-1904). Died at age 4.
• Prince Friedrich of Hesse and by Rhine (1870-1873). Died before his third birthday of bleeding on the brain resulting from a fall from a third-story window (which would almost certainly have been fatal even if he had not had haemophilia).
• Princess Alix of Hesse and by Rhine (1872-1918), later Empress Alexandra Feodorovna of Russia through her marriage to Tsar Nicholas II (1868-1918). Alix had a marriage proposal from her first cousin, Prince Albert Victor (1864-1892), eldest son of the then Prince of Wales (later King Edward VII); had she accepted, haemophilia could have returned to the direct line of succession in Britain.
  • Grand Duchess Maria (1899-1918), Nicholas and Alexandra's third daughter, was thought by some to have been a symptomatic carrier because she haemorrhaged during a tonsillectomy.^[3] DNA testing of the Romanov family remains in 2009 showed that one of the four daughters, thought to be Maria by American researchers and Anastasia by Russian researchers, was a carrier.^[1]
  • Tsarevitch Alexei (1904-1918) was murdered with his family by the Bolsheviks at the age of 13. Alexei's haemophilia was one of the factors contributing to the collapse of Imperial Russia during the Russian Revolution of 1917.^[4]
• Princess Marie of Hesse and by Rhine (1874-1878), Alice's seventh and last child, may or may not have been a carrier. She died of diphtheria at the age of four.

Prince Leopold

Leopold (1853-1884), Victoria's eighth child, was the first member of the family to manifest haemophilia; he died at age 30 from bleeding after a minor fall,^[5] only two years after marrying Princess Helena of Waldeck and Pyrmont. (1861-1922)

He passed the gene on to his only daughter, as all of the daughters of a haemophiliac father would inherit the gene:

• Princess Alice of Albany (1883-1981), later Countess of Athlone, who in turn passed it on to her elder son:
  • Prince Rupert of Teck (1907-1928), who died at age 20, bleeding to death after a car accident.

Alice's younger son Prince Maurice of Teck died in infancy, so it is not known if he was a sufferer. Her daughter Lady May Abel Smith (1906-1994), Leopold's granddaughter, has living descendants none of whom has been known to have or to transmit haemophilia.

Leopold's posthumous son, Charles Edward (1884-1954), was unaffected, as fathers cannot pass the gene to a son.

Princess Beatrice

Princess Beatrice (1857-1944), Victoria's ninth and last child, and wife of Prince Henry of Battenberg (1858-1896) passed it on to at least two, if not three, of her four children:

• Princess Victoria Eugenie of Battenberg (1887-1969), later Queen Victoria Eugenia of Spain through her marriage to King Alfonso XIII (1886-1940), who passed it on to
  • Infante Alfonso of Spain, Prince of Asturias (1907-1938). Died at age 31, bleeding to death after a car accident.
  • Infante Gonzalo (1914-1934). Died at age 19, bleeding to death after a car accident.
  • Victoria Eugenie's two daughters, Infantas Beatriz (1909-2002) and Maria Cristina of Spain (1911-1996), both have living descendants none of whom has been known to have or to transmit haemophilia.
• Prince Leopold of Battenberg (1889-1922), later, Lord Leopold Mountbatten. Died at age 32 during a knee operation.
• Prince Maurice of Battenberg (1891-1914). Killed in action in World War I at the age of 23. Maurice's haemophilia is disputed by various sources: It seems unlikely that a known haemophiliac would be allowed to serve in combat.

Today

No living member of the present or past reigning dynasties of Europe is known to have symptoms of haemophilia or is believed to carry the gene for it. The last descendant of Victoria known to suffer from the disease was Infante Don Gonzalo, born in 1914, although dozens of descendants of Queen Victoria's (including males descended only through females) have been born since 1914. However, because the haemophilia gene usually remains hidden in females who only inherit the gene from one parent, and female descendants of Victoria have left many descendants in royal and noble families, there remains a small chance that the disease could appear again, especially among the female-line Spanish descendants of Princess Beatrice.

• Infanta Beatríz's two sons were not affected by the disease. Beatriz's eldest daughter, Sandra, has two children, a son and daughter. Her son is not affected, and her daughter has two sons, who are apparently unaffected. Beatríz's youngest daughter, Olimpia, had six children; her two eldest daughters, Beatrice and Sibilla are both married with children, none of whom, in the case of their sons, appear to be haemophiliacs. If Sibilla's descendants were to express or transmit the gene, however, another reigning dynasty of Europe would, in the 21st century, join the rest of the reigning families that inherited the disease from Queen Victoria. Olimpia's youngest daughters are still unmarried, but there is still a chance they could be carriers. Another daughter, Laura, died as a child, as did her only son, Paul, the latter of whom was apparently not a haemophiliac.
• Infanta Maria Cristina had four daughters, all potential carriers. Her eldest daughter, Vittoria Eugenie, had a daughter and three sons, the latter all apparently unaffected. The Infanta's second daughter, Giovanna, had only one child, an unaffected son. Her two youngest daughters, Donna Maria Teresa and Donna Anna Sandra, also have only daughters. Of these, only one, Maria Teresa's second daughter, Isabel, is married, but she also has only a daughter. There is a chance the disease may remain in this branch of Princess Beatrice's descendants.

Chronological order

Queen Victoria died in 1901 so she lived to see her youngest son and a grandson die from the disease. A great-grandson was diagnosed with the disease as well. The gene can be passed down the female line without a haemophiliac son being born, but as the family line continues and no haemophiliac sons are born, it becomes less likely that a certain ancestor had the gene and passed it on through the female line.

Type of haemophilia discovered

Because the last known descendant of Queen Victoria with haemophilia died in the 1940s, the exact type of haemophilia found in this family remained unknown until 2009. Using genetic analysis of the remains of the assassinated Romanov dynasty, and specifically Tsarevich Alexei, Rogaev et al. were able to determine that the "Royal Disease" is actually haemophilia B. Specifically, they found a single-nucleotide change in the gene for clotting Factor IX that causes incorrect RNA splicing and produces a truncated, nonfunctional protein.^[6]

Notes

References and external links

• Potts, D. M. Queen Victoria's Gene. Sutton Publishing, 1999. ISBN 0-7509-1199-9.
• "Hemophilia: The Royal Disease"
• Family tree of Queen Victoria and her descendants
• Another family tree