This chapter provides answers to these questions · health problems, hemophilia can be passed from generation to generation. In almost all cases, the gene responsible for hemophilia

How a Child GetsHemophilia2

This chapter provides answers to these questions:

� What is genetics?

� How do genes decide the sex of children?

� Is it true that only males get hemophilia?

� How is hemophilia passed from parents to children?

� Does hemophilia always run in families?

� Why are women carriers? Do they ever get hemophilia?

� What is carrier testing?

� What is pre-natal testing and who should have it?

� Should parents take any special steps at the baby’s birth,

if they know their child will have hemophilia?

� How soon after birth can a baby be tested for hemophilia?

� What are the issues related to pre-natal testing?

David Lillicrap, M.D., FRCP(C)Professor, Departments of Pathology and Medicine; Director, Regional Hemophilia Program, Queen’s University, Kingston, ON

Maureen Brownlow, RSWSocial Worker, Bleeding Disorders Clinic, IWK Health Centre, Halifax, NS

2How a Child GetsHemophilia

NOTES

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All About Hemophilia

� Introduction

Hemophilia is a genetic disorder. This means that it is caused bya gene that does not work the way it should. Like other genetichealth problems, hemophilia can be passed from generation togeneration. In almost all cases, the gene responsible forhemophilia is passed from a parent to the child at thetime of conception.

In order to understand hemophilia, you need to know aboutgenes and genetics. If there is a history of hemophilia in yourfamily, you may want to know:

• Am I likely to pass hemophilia on to my child?• Am I a carrier of hemophilia?• Could my daughter be a carrier of hemophilia?

The purpose of this chapter is to give you some basic informationabout genes and genetics, and how hemophilia is passed fromparents to children. Because genetics can be hard to understand,we suggest you talk to the genetic counselor at a hemophiliatreatment centre (HTC). This person has the knowledge andtraining to answer all your questions.

� What is genetics?

Genetics is the study of how genes arepassed from one generation to thenext. Each cell inside your bodycontains genes. They store, and passalong, information that makes youunique.

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“My brother has

hemophilia and I

don’t. He gets mad

if I tell him my

genes are better than

his. I feel bad for

him when he is

hurt. Other times he

is just my younger

brother.”

Here’s how it works:

• Inside the cell nucleus is a group of structures calledchromosomes.

• Each chromosome is made up of a long chain of a chemicalcalled DNA (deoxyribonucleic acid). The DNA in eachchromosome is arranged in thousands of units called genes.There are between 30,000 and 40,000 genes in each cellin your body.

• Each one of your genes is in charge of telling your body toproduce certain proteins. Some genes decide the colour ofyour eyes. Others determine whether you are male orfemale, how your blood clots, etc.

Each person has a pair of chromosomes called the sexchromosomes. They decide whether you are male or female.Women have two X chromosomes––this is what makes themfemale. Men have an X chromosome and a Y chromosome––this makes them male.

The genes that take care of production of factor VIII and IX arepart of the X chromosome. They play an important role in howhemophilia is passed from person-to-person in families. (Seethe section called What is carrier testing? later in this chapter tolearn more about new tests that can tell women whether or not theycarry the hemophilia gene.)

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MYTH: BOYS ALWAYS GETHEMOPHILIA FROMTHEIR MOTHERS.

REALITY: It is true that in mostcases the gene respon-sible for hemophilia istransmitted frommother to son at themoment of conception.However, in othercases, hemophilia iscaused by a newgenetic mutation inthe chromosomes ofthe child. The motherdoes not carry thegene. No other familymembers are affected.

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� How do genes decide the sex ofchildren?

When a man’s sperm (X or Y) and a woman’s egg (one oftwo X’s) meet, there are four ways the egg and spermcells can combine. Figure 1 shows what can happen.

The woman’s egg contains an X chromosome. The man’s spermcontains either an X or a Y chromosome. A woman’s egg ONLYhas X chromosomes to give to a child. Therefore, it is the man’ssperm that determines the sex of a child because he can add eitheran X chromosome or a Y chromosome to the woman’s Xchromosome. In other words:

• If the sperm cell that reaches the egg contains an Xchromosome, the child will be a girl.

• If the sperm cell that reaches the egg contains a Ychromosome, the child will be a boy.

“I have hemophilia

and my brother

doesn’t. Sometimes

that bugs me.

My sister can give

it to her kids when

she has babies and

she’s older than me.

I’m going to be

really nice to her

kids if they are boys

and then I will have

someone to help.” Figure 1

� Is it true that only males get hemophilia?

This is almost always true. Here’s why it works this way.

Each human being gets half of his/her chromosomes from eachparent. This means that the sex chromosomes inside each cellin your body come from both your mother and father.

As you know, the genes that help to produce factors VIII and IXare found on the X chromosome. Females have 2 copies of anX chromosome in each cell. Males have only one.

When a gene has a mistake in its structure, it is called a mutantgene. The mistake itself is called a mutation.

Because a male has only one copy of the X chromosome in eachcell, the mutation (or mistake) that causes problems with factorVIII or IX is certain to affect him.

On the other hand, because a female has two X chromosomes,one of those X chromosomes will be normal. This normal Xchromosome protects a woman from the severe form ofhemophilia, even though some women may have more bleedingthan a normal person.

A girl can be born with severe hemophilia only when…

• a woman who carries the hemophilia gene has a child with aman who has hemophilia

• a woman who is a carrier has a child with a normal man anda second new hemophilia mutation happens when the childis conceived.

• a man who has hemophilia has a child with a normalwoman and a second new hemophilia mutation happenswhen the child is conceived.

These three situations are extremely rare.

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“Mom and I are

both affected by

hemophilia. She has

the defective gene

too and she has

bleeding problems.

She has more factor

VIII than I do. She

didn’t get needles

when she was a kid.

She understands

how I feel when I’m

hurt because she

used to have really

bad nose bleeds.”

� How is hemophilia passed from parentsto children?

When a man with hemophilia has children with a woman whodoes not carry the hemophilia gene, all their sons will be normal.This is because the father passes along his normal Y chromosometo his sons. All their daughters will carry the hemophilia gene.This is because the father has passed along his abnormal Xchromosome to them. See Figure 2.

The daughters of this couple will not have hemophilia but theywill have the mutant gene that carries hemophilia. They arecalled carriers.

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MYTH:

ONLY MALES HAVEHEMOPHILIA

REALITY:

It is true that not

many females have

the severe forms of

factor VIII and IX

deficiency, although

there are a few known

cases. However,

many female carriers

suffer from symptoms

of mild hemophilia,

especially menorrhagia.

What’s more, just as

many females as

males have von

Willebrand disease,

a very common

bleeding disorder, and

women’s symptoms

are often worse. Figure 2

= the hemophilia gene

Let’s go to the next generation of this family. The daughter whocarries the mutant X chromosome is having children with a manwho does not have hemophilia. Figure 3 shows what mayhappen in this case.

The drawing shows all the possible outcomes. Each time thiswoman gets pregnant there is the same 1-in-4 chance that oneof these results will happen.

Most people who have hemophilia inherit it from a mother whocarries the mutant gene. That’s why hemophilia is called aninherited condition.

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“I grew up with

a brother with

hemophilia. I was

upset when our

son was diagnosed

because I knew

how hard it could

be. For our son,

prophylaxis

treatment has

completely changed

the expectation of

what I thought life

would be like for

him. He plays

badminton,

soccer, and swims

competitively.

My brother’s life

was more limited.”

Figure 3

� Does hemophilia always run in families?

In about 3 out of 10 cases, a son will be born to a family thathas no history of hemophilia. There are 3 reasons why thismight happen:

1. It could be that “silent” hemophilia was part of the familyfor generations. Because no male showed signs of increasedbleeding, no one believed hemophilia was present. The familymay have had girls who were hemophilia carriers. But if noneof these girls had sons, or none of the sons had hemophilia,no one would know that hemophilia was being passed on—until a boy was born with hemophilia.

2. It could be that the boy’s mother got the mutant gene at thetime she was conceived. The mother will be the first person inthis family to carry hemophilia. Her children may end up ascarriers or actually have the disease. (See Figure 3 to seewhat may happen when this woman has children with a man whodoes not carry the hemophilia gene.)

3. It could be that the mutation that causes hemophiliahappened when the boy was conceived. In this case, the eggfrom his mother developed a mutation that was passed on tohim. In such a case, the mother is not a carrier. None of herother children will be affected by hemophilia.

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“We were so

shocked when our

son was diagnosed.

We didn’t know

anything about

hemophilia. How

come he had it?

We were terrified.”

Cousins withhemophilia

� Why are women carriers?Do they ever get hemophilia?

A carrier is a woman who has the mutant genethat causes hemophilia.

A woman is a carrier because one of her two Xchromosomes carries the mutant factor VIII or IXgene. The other chromosome is normal and itwill do the job it is supposed to do. In other words, it will sendthe woman’s body a message to producefactor VIII and IX.

Most carriers produce almost normal amounts offactor VIII and IX. But about 1 in 10 carriers hasonly about one-third the normal amount offactor. These women bleed more oftenthan normal women do. They have signs of mildhemophilia, for example:

• They bruise easily.

• They often have nose bleeds.

• They have heavy or prolonged bleeding during their periods(heavy menstrual bleeding).

• They bleed a lot after they suffer a bad cut, get a tooth pulledor have an operation.

Very rarely, a carrier may have an even lower amount of clottingfactor and, in these cases, they will have a further increased riskof bleeding.

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� What is carrier testing?

Carrier testing for hemophilia lets women know whether or notthey carry the mutant gene that causes hemophilia.

We know that all daughters of a man with hemophilia willbe carriers.

But what if you are the daughter of a carrier mother? There is a1-in-2 chance that you will carry the gene for hemophilia. Youare called a potential carrier.

Two kinds of blood tests can be done to find out whether or notyou are a carrier.

1. Coagulation Testing

A lab can measure the way blood clots using asimple blood test called a coagulation test.The results are known in 48 hours.

Because women who are carriers have onlyone normal X chromosome, their blood willoften have less clotting action than the bloodof normal women. The problem with thiskind of testing is that many female carriershave normal rates of clotting action. Thismeans that the testing only gives clear results for about 8 out of10 women.

Although this kind of testing has been used for years, it is nota sure way to find out if a woman is a carrier of hemophilia.

2. DNA testing

Since 1982, scientists have come to a more precise understandingof the genes that help to produce factors VIII and IX. Doctorscan now do more accurate testing to help women find out if theyare hemophilia carriers.

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Here’s how DNA testing works. The tests are done on blooddonated from family members. After the DNA is obtained frominside the blood cells, the structure of the factor VIII and IXgenes is analyzed using a complex set of steps. This kind oftesting can take from several days to several months to complete.

There are 2 kinds of DNA testing.

• DNA Polymorphism Testing: This kind of testing tracksgenetic markers (or polymorphisms) that are close to, andfollow, the mutant genes that cause hemophilia. It is the mostcommon kind of DNA testing used today.

To do this kind of testing, you will need to supply your ownblood (if you are a person with hemophilia or a potentialcarrier). Other key members of your family, including at leastone person who has hemophilia, will also need to supply bloodfor testing. Staff at your HTC will give you advice about whichfamily members should be tested.

This kind of testing provides very accurate results. In a familywith a history of hemophilia A or B, about 95 percent ofpotential carriers will get test results that are 99 percentaccurate. In order to obtain this kind of success with thetesting, it is very important that all key family members betested and that all the family tree information be correct.

• Direct Mutation Testing: In the last couple of years,scientists have learned a lot more about the mutations (geneticchanges) that affect how factors VIII and IX are produced.

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It is now possible to test DNA samples from people withhemophilia and from carriers to see whether the hemophiliamutation is present, or not. This kind of testing will be helpfulbecause:

– not all family members will have to be tested

– in a family where there is no history of the disease, onlythe person who has hemophilia will need to be tested

– it may provide clues about how to treat hemophilia asthe test will show the exact gene mutation.

Because this type of testing is complicated and the factor VIIIand IX genes are large, in 5 to 10 percent of cases this form oftesting will still not identify the hemophilia mutation. Testresults will take a minimum of 5 to 6 weeks to complete.

� What is pre-natal testing andwho should have it?

If a pregnant couple wants to know whether their baby has thegene that causes hemophilia, they can have the fetus tested whileit is still in the womb. This is called pre-natal testing.

The lab tests that will be done on the child’s cells are the same asthe DNA tests that are done to see if a woman is a carrier, namelyDNA Polymorphism Testing or Direct Mutation Testing.

(See the section called What is carrier testing?)

If you are a person with hemophilia who is planning to havechildren, your comprehensive care team can give you detailsabout the kinds of tests that exist. A genetic counselor can alsohelp you look at your choices and decide how to proceed.

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“I didn’t choose tohave pre-nataltesting. We knewwhat hemophiliawas all aboutalready. We havechildren withhemophilia. Ourlast child is a girl. I celebrated hergender as our firstgirl and as a childwithout hemophilia. She might be acarrier. Some day wewill look into this. It isn’t importantright now. I wasmore relieved than I thought I would be.”

Each couple is different and has the right to decide whether pre-natal testing is best for them, or not. Many doctors will suggestthat a woman be tested to see if she is a carrier before she getspregnant. This makes good sense because it may mean that pre-natal tests will not be needed if it is found that the mother isnot a carrier.

The two pre-natal tests that can tell whether a child has orcarries the hemophilia gene are:

Chorionic Villus Sampling (CVS): This test is a form ofgene testing that can be done sooner in the pregnancy thanamniocentesis. CVS can be done 9 to 10 weeks after conception.A very small sample of the chorionic villus (part of the placenta)from inside the womb is taken out and tested in the lab. The riskof miscarriage after having CVS is very low.

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This diagram shows transcervical chorionicvillus sampling using a suction catheter.The procedure is performed underultrasound guidance.

Amniocentesis: This test has been used for many years. The testis usually done about 16 weeks after conception. A small sampleof fluid from the amniotic sac inside the womb is taken out,using a needle. The amniotic fluid contains cells from the fetus(the baby inside the womb). The risk of having a miscarriageafter the test is low––about 1 in 200.

The DNA from the fetal cells is tested for the mutation thatcauses hemophilia.

In all cases where a woman carrier has pre-natal testing, labtests should be done to measure her levels of factor VIII or IX.This is especially important if the carrier has symptoms ofincreased bleeding.

� Should parents take any special steps atthe baby’s birth, if they know their childwill have hemophilia?

If pre-natal tests show that your child will have hemophilia, youshould talk to the doctor who will help to bring the baby into theworld. You should plan for a natural birth (where the baby isborn from the mother’s vagina).

The doctor should not:

• try to deliver the baby using forceps

• use suction on the top of the baby’s head to pull it out of thevagina (also known as vacuum extraction).

You should only have a caesarian birth (where the baby is bornafter an operation that cuts open the woman’s womb) if:

• the birth process goes on for a long time,

• a problem happens that makes the birth very difficult.

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� How soon after birth can a baby be testedfor hemophilia?

It depends on what kind of hemophilia the child has. A bloodtest can tell if a child has hemophilia A or severe hemophilia Bas early as the first day of life.

To find out if a child has mild hemophilia B, you may need towait until the baby is 2 or 3 weeks old. This is because factor IXlevels are low in all babies right after birth.

� What are the issues related topre-natal testing?

If you are a man with hemophilia or a woman carrier ofhemophilia, you and your wife/husband may want to talk to agenetic counselor about pre-natal testing. A genetic counselorunderstands genetic testing and is trained to work with coupleswho are planning to have a baby, or who are already pregnant.Genetic counseling is private, and is carried out in a way thatrespects any decision a couple makes.

The genetic counselor spends time with a couple, listening totheir reasons for having the testing done. If pre-natal testingshows that the baby has hemophilia, the counselor will tell theparents what their choices are. The counselor will also provideinformation about the kinds of care and treatment that existfor children with hemophilia.

Because the decision to have a child is very important, couplesare given time to think over their choices. Genetic counselors aretrained to help couples look at very basic questions, such as:

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“We decided to

have our son

circumcised.

The procedure

seemed to go well

until the bleeding

wouldn’t stop.

The pediatrician

suspected

hemophilia right

away. It was very

traumatic for all

of us.”

• What is their experience with hemophilia?

• What do they know about current treatments for the disease?

• How will having a child with hemophilia affect children theyalready have?

• Does the couple have access to medical care?

• Will the couple have support from family and friends?

Often, the couple have different points of view. Sometimes, thisis based on the fact that one of them has lived with hemophiliaand knows how the medical system works. If a couple decidesthey would like to reach agreement, they can work with:

• a counselor

• a psychologist

• a social worker

• other staff at the HTC

• clergy at a hospital

• a spiritual leader from their own church.

Based on all the information they have, some couples decidethat they will be able to deal with the future needs of a son withhemophilia. They will be able to pass on what they have learnedabout hemophilia to the team that delivers their baby.

Other couples may choose to end the pregnancy. In most cases,when a couple decides to end a pregnancy, the genetic counselorwill be able to refer them to a doctor who can perform theoperation (a gynecologist). If the genetics clinic and the HTC arein a hospital that does not offer this choice, such as a hospitalrun by a religious order, the couple may ask for an appointmentwith a gynecologist outside that system, or they may choose tocontact a family planning clinic that will provide them with thenames of doctors.

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“I met a woman

who knew she was a

carrier at a chapter

event. Her memories

of growing up

included memories

of a father with

chronic pain. Her

Mom encouraged

her to come to a

family event to meet

younger parents

with children with

hemophilia. Her

Mom told me the

time with the young

families and the

children had a very

big impact on her

daughter. She hoped

her daughter would

decide to become

pregnant and feel

good about it.”

Many Canadian hospitals that help couples end a pregnancybecause the fetus has a health problem also offer support to thosecouples. Because it is a hard choice to make, couples may wantto talk to a counselor about their feelings. The man and womancan do this as a couple, as individuals or as part of a group withother couples who have made the same choice. Sometimes, thehospital can suggest books that will offer support. If yourhospital does not offer any follow-up support, you may need toseek it out through your regional HTC or the CanadianHemophilia Society.

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Your son hashemophilia. You are curious aboutyour eventualgrandchildren. How will they beaffected byhemophilia? Whatare the chances ofyour son’s childrenhaving hemophilia?Of being carriers ofhemophilia?

(For some help infiguring out theanswers, see Figure 2on page 2-5.)

(The correct answersare on page 13-17.)

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This chapter provides answers to these questions · health problems, hemophilia can be passed from generation to generation. In almost all cases, the gene responsible for hemophilia