Page 1 Hemophilia by Aronova-Tiuntseva and Herreid

by
Yelena Aronova-Tiuntseva and Clyde Freeman Herreid
University at Buffalo
State University of New York
NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE
Hemophilia:
The Royal Disease
Hemophilia is an X-linked recessive disorder characterized by the inability to properly form blood clots. Until recently,
hemophilia was untreatable, and only a few hemophiliacs survived to reproductive age because any small cut or
internal hemorrhaging after even a minor bruise were fatal. Now hemophilia is treated with blood transfusions and
infusions of a blood derived substance known as antihemophilic factor. However, the treatment is very expensive and
occasional problems can arise because of a patients allergic reactions or other transfer complications.
Hemophilia afects males much more frequently (1 in 10,000) than females (1 in 100,000,000). Tis occurs because
a critical blood clotting gene is carried on the X chromosome. Since males only carry one X chromosome, if that
is defective, hemophilia will immediately show up. An early death is likely. Females, on the other hand, carry two
X chromosomes. If only one is defective, the other normal X chromosome can compensate. Te woman will have
normal blood clotting; she will simply be a carrier of the recessive defective gene. Tis fact will be discovered if some of
her children are hemophiliacs. Naturally, women hemophiliacs are rare because it takes two defective X chromosomes
in order for the condition to be seen.
Hemophilia has played an important role in Europes history, for it suddenly cropped up in the children of Great
Britains Queen Victoria. It became known as the Royal disease because it spread to the royal families of Europe
through Victorias descendants. Queen Victoria had always been worried about the quality of the blood of the British
royal family. Her feelings about the necessity of revitalizing what she called the lymphatic blood of their houses are
refected in her letter to her daughter Vicky: I do wish one could fnd some more black eyed Princes and Princesses
for our children! I cant help thinking what dear Papa saidthat it was in fact when there was some little imperfection
in the pure Royal descent that some fresh blood was infused For that constant fair hair and blue eyes makes the
blood so lymphatic it is not as trivial as you may think, for darling Papaoften with vehemence said: We must
have some strong blood.
It is doubtful that at the time of writing this letter, the Queen knew exactly what was wrong with her familys blood.
Hemophilia frst appeared in Victorias family in her eighth child, Prince Leopold, Duke of Albany. Troughout his
short life, Leopold had sufered severe hemorrhages, and always was described as very delicate. Leading the life of a
normal child was impossible for Leopold because any cut or bump could lead to death and it was necessary to keep
him always under strict surveillance. However, in spite of all the protection, Prince Leopold died at the age of thirty-
one as the result of a minor fall.
Te appearance of hemophilia in one of Victorias sons upset and confused the Queen, who could only protest that
the disease did not originate in her side of the family. Yet, a whisper about the curse of the Coburgs was spread
about. Tis curse was supposed to have dated from the early nineteenth century, when a Coburg prince had married a
Hungarian princess named Antoinette de Kohary. A monk, a member of the Kohary family, envied the wealth inher-
ited by the happy couple from the brides father, and cursed future generations of Coburgs with the disease. Of course,
hemophilia afecting Victorias ofspring had nothing to do with the curse. Te traditional view is that there was a
mutation in either her or in a sperm of her father, Edward Augustus, Duke of Kent. From there it spread through the
Royal Houses of Europe as monarchs arranged marriages to consolidate political alliances. We can trace the appear-
ance of hemophilia as it popped up in Spain, Russia, and Prussia by looking at the family tree (Figure 1 next page).
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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE
Page 3 Hemophilia by Aronova-Tiuntseva and Herreid
1. First, lets take a look at Queen Victorias son Leopolds family (see Figure
2). His daughter, Alice of Athlone, had one hemophilic son (Rupert) and
two other childrena boy and a girlwhose status is unknown.
Questions
(a) What is the probability that her other son was hemophilic?
(b) What is the probability that her daughter was a carrier? Hemophilic?
(c) What is the probability that both children were normal?
Fortunately, Leopold was the only one of Victorias sons who sufered
from hemophilia. Her other three sons, Edward, Alfred, and Arthur,
were unafected. Since the present royal family of England descended
from Edward VII, the frst son, it is free from hemophilia. Louise, Queen
Victorias fourth daughter and sixth child, did not have children and her
status as a carrier cannot be assessed. Vicky, the frst child, and Helena,
the ffth child, had children, none of whom was hemophilic, indicating
that the mothers probably were not carriers.
2. Now for the Spanish connection: Victorias youngest child,
Beatrice, gave birth to one daughter, one normal son, and two
hemophilic sons (see Figure 3).
Questions
(a) Looking at the pedigree of the royal family, identify which
of Beatrices children received the hemophilic gene; why can
you make this conclusion?
(b) Notice that Beatrices daughter, Eugenie, married King
Alfonso XIII of Spain and had six children, one of whom
was the father of Juan Carlos, the current King of Spain.
Would you predict that Juan Carlos was normal, a carrier, or
a hemophilic?
3. Queen Victorias third child, Alice, passed hemophilia to the
German and Russian imperial families (see Figure 4, next page).
Of Alices six children, three were aficted with hemophilia. At
the age of three, her son Frederick bled for three agonizing days
from a cut on the ear. Eventually, the fow of blood was stanched.
But a few months later, while playing boisterously in his mothers room, the boy charged headlong through an open
window and fell to the terrace below. By the evening he was dead from the internal bleeding.
Alices daughter Irene, a carrier, married her frst cousin, Prince Henry of Prussia, and gave birth to two hemophilic
sons. Every attempt was made to conceal the fact that the dreaded disease had shown itself in the German imperial
family, but, at the age of four, Waldemar, the youngest of the princes, bled to death. Te other prince, Henry, died at
the age of ffty-six.
Alices other daughter, Alix, was also a carrier. Had she accepted the ofer of marriage from Prince Eddy, or his
brother George, hemophilia would have been re-introduced into the reigning branch of the British royal family. But
Alexandra (Alix) married Tsar Nikolas II instead and carried the disease into the Russian imperial family. She had
four daughters, Olga, Tatiana, Marie, and Anastasia, before giving birth to the long-awaited son, Alexis, heir to the
Russian throne. Tese children, along with their parents, were eventually murdered during the Russian Revolution.
Within a few months of his birth, his parents realized that their precious and only son, Alexis, had hemophilia. Te
frst sign had been some unexpected bleeding from the navel, which had stopped after a few days. Much more serious,
?
Leopold
Rupert Lady May
Albel Smith
Alice of Athlone
Helen
Figure 2. Leopolds family
JC
Henry Beatrice
Alfonso XIII
of Spain
Eugenie Leopold Maurice
Gonzalo Alfonso
Juan Carlos
of Spain
Figure 3. Beatrices family
NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE
Page 4 Hemophilia by Aronova-Tiuntseva and Herreid
however, were the dark swellings that appeared each time the child bumped an arm or a leg. And worst of all was the
bleeding into the joints. Tis meant a crippling of the afected limbs in addition to excruciating pain. As the boy grew
older, he was obliged to spend weeks in bed, and after he was up, to wear a heavy iron brace.
Neither well-experienced doctors nor numerous prayers to God by desperate parents seemed to help the sufering child.
Distressed over their sons condition, his parents, the Tsar and Tsarina, turned to the monk Rasputin, a spiritualist
who claimed he could help Alexis. Rasputin received an unlimited trust from Alexandra because he was the only
person who was able to relieve her sons suferings. How he managed to do this is uncertain. A likely explanation
is that Rasputin, with his hypnotic eyes and his self-confdent presence, was able to create the aura of tranquillity
necessary to slow the fow of blood through the boys veins. Where the demented mother and the dithering doctors
merely increased the tenseness of the atmosphere around the sufering child, Rasputin calmed him and sent him
to sleep. While Tsar and Tsarina were preoccupied with the health of their son, the afairs of state deteriorated,
culminating in the Russian revolution. Alexis did not die from hemophilia. At the age of fourteen he was executed
with the rest of the family. His four oldest sisters were also young and didnt have children, so we dont know whether
any of them was a carrier. But we can make an estimate.
Questions
(a) What are the probabilities that all four of the girls were carriers of the allele hemophilia?
(b) Supposing Alexis had lived and married a normal woman, what are the chances that his daughter would be a
hemophiliac?
(c) What are the chances his daughters would be carriers?
(d) What are the chances that his sons would be hemophiliacs?
Alice Louis of Hesse
Irene Henry Fred Alix Nikolas II
of Russia
Prince
Sigmund
of Prussia
Waldemar Henry Olga Tatiana Marie Anastasia Alexis
Figure 4. Alices famiy
4. In 1995, a sixty-three-year-old man named Eugene Romanov, a resident of the former Soviet Union, turned up. He
shared both the disease and his last name with the royal family of czarist Russia. He proclaimed himself a grandson
of Nikolas IIs youngest daughter, Anastasia, whose body had at that time not been recovered, and who was believed
by some to have managed to survive the revolution. Eugene Romanov claimed Anastasia was raised by a farmer, and
later she married a nephew of her adopted parents and had a daughter, Eugenes mother.
Questions
(a) According to Eugenes argument, what was the likely hemophilic status of Eugenes mother and grandmother?
What about his father and grandfather? Is this argument plausible?
(b) How plausible is it that Eugene inherited both hemophilia and the last name from the royal family? (Hint: Look
how each of them is passed from generation to generation.)
NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE
Page 5 Hemophilia by Aronova-Tiuntseva and Herreid
2
Case copyright held by the National Center for Case Study Teaching in Science, University at Bufalo, State University of New York. Originally
published 1999; last updated 2003. Please see our usage guidelines, which outline our policy concerning permissible reproduction of this work.
5. Prince Charles is the designated next king of England (see Figure 5). His well publicized marriage to Princess Diana
produced two sons before it ended in an acrimonious divorce.
Question
If you learned that one of the two sons was a hemophiliac, what are the possible explanations for this event?
References
Aronson, T. 1973. Te Royal Disease, in Grandmama of Europe: Te Crowned Descendants of Queen Victoria, pp. 170180.
Meacham, J. and D. Pedersen. 1995. Was Queen Victoria a bastard? Newsweek July 24: 56.
Potts, D.M., and W.T.W. Potts. 1995. Queen Victorias Gene: Haemophilia and the Royal Family. Stroud: Alan Sutton
Publishing.
Victoria
Wilhelm George V
George
VI
Princess
Margaret
Queen
Elizabeth
Frederick Alexandra Edward VII
of England
Sophia
of Greece
Prince Phillip
Princess
Ann
Prince
Charles
Prince
Andrew
Prince
Edward
Figure 5. Prince Charles family
Finally, our speculative natures compel us to mention that in 1995 two British brothers produced a new book (Queen
Victorias Gene) with a breathtaking suggestion. Professors Malcom Potts, an embryologist at Berkeley, and William
Potts, a zoologist at Britains Lancaster University, suggest that Queen Victoria might have been illegitimate. Tey
point out that neither her father nor her husband was a hemophiliac. So either there was a spontaneous mutationa
one-in-50,000 chanceor Victoria is the daughter of someone other than the Duke of Kent. Tink of the possible
consequences to European history: no Victoria, and the current Prince of Hanover, Ernst (descendent of the brother
of Victorias father), would be King of England today. More importantly, no Victoria would mean no hemophilic son
of the Czar of Russia, no Rasputin, and no revolution? What are the chances of this scenario?