Download Arthur Jones is a 44 year old office worker

Scenario 1:
Arthur Jones is a 44-year old office worker. For the past 2 years he has developed
central chest pain on exercise. Initially this was only when walking up steep hills,
although now he gets chest pain walking up a single flight of stairs. The chest pain
resolves when he takes his GTN spray. He lives on the 4th floor of a tower block in
Lochee, with his wife and 20-year old son John.
After a consultation about a sore throat, Mr Jones mentions that he is worried by his
family history of heart disease. His brother George died at the age of 45 following a
myocardial infarction and his sister Amelia has angina at the age of 33. He has two other
sisters, Mary (age 50) and Louise (age 37) who are both well. Mr Jones tells you that
both his mother and father died from “heart problems”, his mother at age 71 and his
father at 38.
On examination in the clinic, Mr Jones is overweight, weighing 107kg with a height of
173cm. He smells so strongly of cigarette smoke that you have to open your clinic room
window. There are no other findings on cardiovascular examination. His blood pressure
is 120/80.
a)
Answer the questions below. When answering each question think
about which of the basic principles being studied are relevant to the
question.
QUESTIONS
What are the possible causes of Mr Jones’ chest pain?
Draw Mr Jones’ pedigree
What aspects of Mr Jones’ family history are unusual?
What blood tests would you consider to help explain the cause of Mr Jones’ family history
of heart disease?
Mr Jones has a son. What is his risk of inheriting the familial susceptibility to ischaemic
heart disease?
Why is it important to determine the risk of heart disease occurring in other members of
this family?
1
Now consider this additional scenario. Mr Brown had an episode of severe chest pain
when he was 50 years old. Investigations confirmed that he had a myocardial infarction.
His blood cholesterol was 6mmol/l (ideally total cholesterol should be <5mmol/l). His
family tree is drawn below:
How might the cause of heart disease differ in Mr Jones’ and Mr Brown’s families?
What features of their family histories suggest a different cause for heart disease in the
two families?
How would you assess the risk of ischaemic heart disease in Mr Brown’s 45 year old
brother?
b)
Can you think about the curriculum outcomes that may be required to
deal with these scenarios?
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Scenario 2:
Marie is a 22-year old Nigerian working as a nursing assistant in the UK for the last 2
years. She has had numerous episodes of bone pain over the years, mainly affecting her
knees and shoulders, and knows that she has Sickle Cell Disease. She usually manages
to control these painful “crises” by using paracetemol at home together with plenty of oral
fluids. However, on three occasions she has required hospital admission and treatment
with diamorphine analgesia.
Three days ago she developed a further episode of right shoulder pain, associated with
general malaise. This pain was not controlled with simple analgesia, and she developed
a high temperature, sharp pain in her right chest on intake of breath, and felt short of
breath on exertion. She was admitted to the haematology ward, had a chest X-ray which
showed opacification in the lower right lung, and was found to be hypoxic (oxygen
saturation of the blood 89%). She was treated with intravenous fluids, oxygen by face
mask, a diamorphine infusion, and intravenous antibiotics. With no improvement after 24
hours she underwent an exchange transfusion of red cells, after which the proportion of
sickle haemoglobin (HbS) in her blood had fallen from 95% to 40%. She was well
enough to go home 7 days later.
a)
Answer the questions below. When answering each question think
about which of the basic principles being studied are relevant to the
question.
QUESTIONS
How is sickle cell disease inherited?
Did her diagnosis require molecular genetic testing?
What are the altered properties of sickle haemoglobin (HbS) and how does this result in
the clinical picture of sickle cell disease?
What are the possible causes for her chest pain?
Why is she hypoxic and why is hypoxia to be avoided in sickle cell disease?
Why may exchange transfusion of red cells help?
Which ethnic groups have a higher frequency of sickle cell disease and why may this have
occurred?
b)
Can you think about the curriculum outcomes that may be required to
deal with this scenario?
3
Scenario 3
Ian Smith (age 22) develops a severe cough and right sided chest pain. He deteriorates
rapidly and is admitted to intensive care, requiring mechanical ventilation.
Ian was diagnosed as being affected with cystic fibrosis at the age of 3 because of his
slow growth and poor absorption of food. You meet his mother Mary, father John and
sister Claire in hospital where he is being treated.
a)
Answer the questions below. When answering each question think
about which of the basic principles being studied are relevant to the
question.
QUESTIONS
What is the likely cause of John’s chest pain?
What are the clinical features of cystic fibrosis?
How is cystic fibrosis inherited?
What tests can be used to diagnose cystic fibrosis?
John’s sister, Claire, is 12 weeks pregnant when she comes to the clinic with her
boyfriend.
What is the risk that this child will be affected?
What are the options for genetic testing?
Claire opts for prenatal testing. The results are shown. What does this mean for the
pregnancy?
You also perform routine chromosome analysis on the sample. The karyotype is given.
What is the chromosomal abnormality shown?
What are the implications of this chromosome abnormality, and how do you discuss this
with Claire?
b)
Can you think about the curriculum outcomes that may be required to
deal with this scenario?
4
Scenario 4
Fred White (age 45) was having breakfast one morning, when he developed sudden
onset pain in the centre of his chest. On admission to hospital a diagnosis of aortic
dissection was made. He makes a good recovery following urgent surgery and you see
him 5 days post operatively on the ward.
On examination you note that he has long fingers, and long arms and legs in relation to
his body. He also has marked cutaneous striae. You make a diagnosis of Marfan
syndrome.
Following discharge from hospital, Mr White comes to the genetics clinic with his two
sons, James age 16 and John age 18. Mr White has a sister, Jane,who has severe
curvature of the spine, and a brother Arthur who is in good health.
a)
Answer the questions below. When answering each question think
about which of the basic principles being studied are relevant to the
question.
QUESTIONS
Mutations in which gene can cause Marfan syndrome?
How is Marfan syndrome inherited?
What is the risk that James and John are affected?
You take a blood sample from Mr White, and sequence the fibrillin gene. The results are
shown for Mr White and 1 other person from the same family who was tested at the
same time.
What is the mutation causing Marfan syndrome in Mr White and in the other person
tested?
What effect do these mutations have on the fibrillin protein?
James and John want to be tested for the same gene change. What should you discuss
with them before doing the test?
Results for James are shown.
Is James affected?
b)
Can you think about the curriculum outcomes that may be required to
deal with this scenario?
5
Ischaemic heart disease
a multifactorial condition
•
Caused by occlusion of coronary arteries by
atheromatous lesions
Fibrolipid plaques
–
–
Complicated lesions
•Hemorrhage into plaques
•Plaque rupture or fissuring
•Thrombus formation
•Environmental
–Smoking
–Diet
–Exercise
•Associated conditions: susceptibility to each condition
is determined by the interaction of multiple genes and
environmental factors
–Hypercholesterolaemia
–Diabetes
–Hypertension
Estimating risk of coronary heart disease
The computer has an excel spread sheet on it that will calculate the risk of ischaemic heart
disease occuring in the next 10 years.
SBP:
DBP:
Total-C:
HDL-C:
ECG-LVH:
systolic blood pressure (average* ~ 131 mmHg)
diastolic blood pressure (average* ~ 73 mmHg)
total cholesterol level (average* ~ 5.6 mmol/l)
amount of cholesterol in high density lipoproteins (HDL
cholesterol is
protective while low density lipoprotein
cholesterol increases the risk) (average* - 1.3mmol/l)
changes in the electrical activity of the heart indicating
increased strain on the heart muscle
•*Average in men aged 16-64 years
•This model does not take family history into account
Heterozygotes for LDL receptor mutations often have
severe hypercholesterolaemia
Lipoproteins containing cholesterol are removed from the circulation
through binding of apolipoproteins to cell surface receptors. LDLs (low
density lipoproteins) are taken up by cells when the cells’ LDL
receptors bind to apolipoproteins on their surface. Only about 1/500
of us carry an LDL receptor mutation.
Apolipoprotein E and hypercholesterolaemia
• Apolipoprotein E (ApoE) has 3 common variants (alleles)
• apoE4 is associated with increased cholesterol levels but not to the same levels
as are seen in individuals with mutations in the LDL receptor gene
• Frequency of alleles (alternative forms of ApoE) in population
• apoE3
78%
• apoE2
8%
• apoE4
14%
• Several combinations of the ApoE alleles (genotypes) are possible
E2/E2
E3/E4
(22% of population)
E2/E3
E4/E4
(2% of population)
E3/E3
E2/E4
•The ApoE genotypes (E3/E4 and E4/E4) associated with increased cholesterol
are common. Common variants of many other genes also contribute to
cholesterol levels
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Sickle Haemoglobin (HbS)
•Point mutation of β globin gene (chromosome 11)
•Translation of the altered triplet code results in substitution of
glutamine by valine
•Altered properties of resulting β globin and the entire haemoglobin
molecule (α2β2)
•Pathological effects on red blood cell containing the haemoglobin
Geography of HbS (and other haemoglobinopathies)
Common in populations where Falciparum malaria is, or has been,
common
Sickle cell trait (Hb A/S; sickle carriers) relatively protected from
malaria – can you think of possible reasons?
Sickle cell disease patients very vulnerable to malaria.
What proportion of births would you expect to have homozygous
(HbSS; sickle cell disease) in a population where 1 in 10 are sickle
haemoglobin carriers?
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Pathophysiology of sickle cell formation
When deoxygenated, HbS is 50 times less soluble than HbA, and forms long
crystals called "tactoids". These distort the red cell (to form crescent or sickle
cells), initially reversibly. However, after repeated sickling at the low oxygen
tension found in the microcirculation, membrane damage causes permanent
sickling. These more fragile cells are then destroyed (red cell lifespan 10-20 days
compared with normal of 120 days. This causes a chronic haemolytic anaemia with
a haemoglobin concentration of around 6-9g/dl (normal 13-16g/dl).
HbS has lower oxygen affinity than HbA
Increased oxygen delivery to peripheral tissues (where oxygen tension
is low): therefore patients have few symptoms of anaemia.
Figure 1. Diagrams illustrate the pathophysiology of SCA. A shows a
hemoglobin molecule Composed α of two chains and two sickle β chains. In B,
the hemoglobin molecules bind together across β chains, forming a strand of
hemoglobin molecules. In C, other hemoglobin molecules bind to the strand,
creating a large polymer. In D, the RBC is distorted by the rigid polymers within
into an elongated, sickle shape. In E, the sickled RBCs obstruct small vascular
channels.
BUT
Deoxygenated HbS is much less soluble, leading to red cell sickling in
peripheral tissues, vessel obstruction and tissue damage
Chest Syndrome in Sickle Cell Disease
Effects of sickling
Acute chest syndrome
• Rigidity and sickling of red cells leads to increase in blood
viscosity and slowing of blood flow.
• Local blood vessel obstruction leads to tissue hypoxia
producing further deoxygenation which promotes further
sickling.
•Shortness of breath
•Cough,
•Blood in sputum,
•Pleuritic chest pain
•Chronic effects of repeated episodes
• This leads to cell death and tissue infarction at the site of
obstruction.
•This is called “Sickle Crisis” and results in bone pain and/or
organ damage (e.g. bone, lung, brain, kidneys)
•Impaired lung function
•Pulmonary hypertension
•Respiratory failure.
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Diagnosis
Morphology of red blood cells:
Blood film
Properties of altered haemoglobin:
Different electrical charge. Separation by:
Electropheresis
High Performance Liquid Chromatography
Solubility of haemoglobin
Genetic testing - antenatal diagnosis
Patient HbSS (Sickle Cell Disease)
Lane 1 – Normal
Lane 4 – HbAS (Sickle Cell Trait)
Treatment
Management of Sickle Cell Disease (HbSS)
Oxygen – avoid deoxygenation and further sickling of red cells
Intravenous fluids – avoid hyperviscosity of blood
Analgesia – relieve pain of tissue infarction, e.g. in bone
Red cell transfusion/exchange transfusion – reduce proportion of HbS in
blood
Stimulate HbF (fetal haemoglobin, a2g2) production - reduce interaction
between HbS molecules, and thus reduce insoluble tactoid formation and
sickling of red cells, e.g. with Hydroxycarbamide therapy.
Sickle Cell Trait (HbAS) is normally asymptomatic
BUT:
•avoid severe hypoxia
•1:4 risk of having a child with HbSS if partner also has Sickle
Cell Trait
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a teenager's story
by Sarah Gordon
The following speech was given by Sarah Gordon at the Zellers Home Office Golf Tournament, June 2001. It is
published with Sarah's permission
Hello everyone my name is Sarah Gordon, I am fifteen years old and I have cystic fibrosis. I am one of the Zellers CF
poster children for the year 2001. I was asked to speak about what exactly cystic fibrosis is and what it is like to live
with. Okay, so what is CF? CF is a genetic disorder that mainly affects the lungs and pancreas. I have to do an hour
and a half of therapy to help loosen the mucus that clogs my lungs everyday and take about 40 pills just to survive. I
take about 30 pancreatic enzymes everyday due to my inability to digest everything, but simple sugars because of CF.
The other pills I mentioned are multivitamins, supplements, and calcium because I still have difficulty obtaining all of the
nutrients from food even though I take pancreatic enzymes. I also must visit a CF doctor at Sick Kids (Toronto's
Hospital fo Sick Children) every three months in order for them to monitor my disease. My CF therapy is difficult to do
because it takes a lot of time and effort, but it is a small price to pay for an extended life. Did you know that the life
expectancy for a CF person is about 30 years of age? I am middle aged and I haven't even graduated from high school.
Now I can move on to what it is like to live with such a horrible disease. As you can imagine, it is difficult to not be
"normal" especially as a teenager, I try to live an "average" life by hanging out with my friends, maintaining good grades
in school, and playing sports. It is an ongoing struggle that keeps getting harder. It is so hard to describe what living
with CF is like, so I will make some comparisons in hope you will be able to relate to me a little easier. Having cystic
fibrosis is like being in a bad dream and not being able to wake up. That is, until there is a cure. It's knowing how hard
you work for a day that may never come. For a day in the future. It's like having dreams that may never come true
because you may not live long enough. What's a dream called if it never happens? A mirage? Having CF is like starting
a race a minute too late. You still work hard to win, and have hope, but realistically, you know you probably won't be
able to win. I try to be really optimistic about CF, but like in the race, it's hard when you have drawbacks, such as when
you are ill and have to be hospitalized. Since I was diagnosed with cystic fibrosis at age 3 and a half, I have been
hospitalized due to my CF at least one time every year of my life, except for last year. I thought I was finally pulling
ahead in the race, but just last week I was in the hospital. I was on an Ibuprofin study to see if it would stop the
inflammation in my lungs due to CF. I was ordered to take 10 pills a day, and they did many tests to make sure my
body could handle that much Ibuprofin. After 2 years, it turns out my body can't handle 10 Ibuprofin a day and I had
internal bleeding in my stomach. I was seriously ill and almost needed a blood transfusion. Luckily, I am okay now, but
still recovering.
Unfortunately I cannot go back to school to finish the year, so I have to write my exams during my summer vacation.
When I was told I had CF, and was old enough to really understand it, no one told me it was going to be easy, but I
didn't expect it to be this hard. At age 12, I was just starting to realize what having CF meant. This was a really difficult
time because I had just started junior high school and I had all new friends. Of course, with having new friends, no one
knew I had CF and I was too scared to tell them because I was worried about how they would react, I also enjoyed
being "normal" because everyone thought I was just like them. To everyone else, I was just another person. Now, only
my close friends know about CF and I like it that way. At home, I have to do all my therapy, take my pills, and be a CF
person, but at school I can just be a teenager. No special treatment. No medication. No worries. Well, I am a teenager,
so almost no worries. A lot of people ask me why I don't tell everyone about having cystic fibrosis. My answer is easy. I
say "I like being just another face in the crowd." I have never been like everyone else before, but now I am and it's
something I have dreamed of my whole life. Pretty strange dream, huh? A dream to be like everyone else? Not much of
a dream to most people, but its a huge deal to me. I can't wait for the day when there is a cure and I am like everyone
else, for real.
I want to thank everyone here for their time, money, and support. I know that you aren't the ones who have CF, and you
are doing all of this for other people like me and I just can't thank you enough. I also want to give a special thanks to
Zellers. They are trying so hard to make my dream of being CF free come true. They are a group of amazing people
and on behalf of all people with CF, we cannot thank them enough. I wish that I could repay them somehow.
Life is hard and I am prepared to deal with it, just as long as I am able to. In spite of all I have been through, I made a
promise to myself. I promised myself I will never give up the fight! And I never will!
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Down Syndrome
Patient Surname: Doe
Prename: Mary (Fetus of)
Dob: 01/01/80
Consultant: Dr. J. Berg, Consultant Clinical Geneticist, Ninewells
Amniotic Fluid Report
Karyotype: 47,XY,+21
Abnormal male karyotype with an additional chromosome 21, as seen in
Down syndrome.
Whatever the outcome of this pregnancy, please send appropriate followup samples to the laboratory in order to confirm the karyotype.
As a previous trisomic conception confers a slight increased risk of
recurrence, fetal karyotyping should be considered in a future pregnancy.
The results of molecular studies for cystic fibrosis status will be reported
separately by our molecular genetics section.
CP2,Area3/4
Sweat Test
Test Overview
A sweat test is done to help diagnose cystic fibrosis by measuring the amount of salt chemicals (sodium and chloride) in sweat. Normally, sweat on
the skin surface contains very little sodium and chloride. People with cystic fibrosis have 2 to 5 times the normal amount of sodium and chloride in
their sweat. See an illustration of a normal sweat gland.
During the sweat test, medication that causes a person to sweat is delivered through the skin. The sweat is then collected on a paper or a gauze
pad and the amount of salt chemicals in the paper or gauze is measured in a lab. Generally, chloride is measured. See an illustration of a sweat
test.
Why It Is Done
The sweat test is done to help diagnose cystic fibrosis. It is usually done shortly after birth for a child who may have cystic fibrosis. A first test may
be done as early as 48 hours of age. If it indicates that the child does not have cystic fibrosis (negative test), a second test may be done when the
baby is older than 4 weeks. Younger babies may not produce enough sweat to give reliable test results and may have lower sweat chloride levels
than older babies and children with cystic fibrosis.
A sweat test may be done for people with a family history of cystic fibrosis and for anyone with symptoms of cystic fibrosis.
How To Prepare
Do not exercise strenuously or get extremely hot before having a sweat test. No other special preparations are required.
If possible, one or both parents or another adult should remain with a child during the test. It may comfort the child to bring along a favorite toy or
item (such as a blanket) to help pass the time while the sweat test is done.
Talk to your health professional about any concerns you have regarding the need for the test, its risks, or how it will be done. Complete the medical
test information form to help you understand the importance of the test.
How It Is Done
The sweat test is usually done on an infant's arm or thigh. On an older child or adult, the test is usually done on an arm. Sweat is generally
collected and analyzed from two different sites to assure quality of the test.
The skin is washed and dried, then two small gauze pads are placed on the skin. One pad is soaked with a medication (pilocarpine) that makes the
skin sweat; the other pad is soaked with salt water. Electrodes that are hooked up by wires to an instrument are placed over the pads. The
instrument produces a mild electric current for 5 to 10 minutes that causes the medication to enter the skin.
After the medication is delivered, the gauze pads and electrodes are removed and the skin is dried. The skin will have a reddened area about 1
in.(2.5 cm) across where the medicine was delivered.
A dry gauze pad, paper collection pad, or special tubing is then taped to the red patch of skin. This pad is coated with plastic or wax to prevent
evaporation. After it soaks up the sweat for up to 30 minutes, it is removed and placed in a sealed bottle. Later it will be weighed to measure how
much sweat the skin produced and analyzed to determine how much salt chemical (sodium or chloride) the sweat contains.
After the collection pad is removed, the skin is washed and dried again.
The sweat test takes 45 minutes to an hour.
How It Feels
The child will feel a light tingling or tickling when the electric current is applied. There should be no pain. If the child cries or seems to be in pain, the
gauze pads will be checked. If they are not properly placed, the electric current may produce a burning sensation.
The test site may be red and continue to sweat for several hours after the test.
Risks
There is almost no risk of electrical shock from this test. However, it should always be done on an arm or leg (not the chest) to prevent the electric
current from affecting the heart.
The electric current may cause skin redness and excess sweating for a short time after the test is done. Rarely, the current may cause a slight burn
on the skin.
Results
Adults generally have higher sodium and chloride concentrations in their sweat than children. Also, sweat test results in adults can vary widely. This
is especially true in women, because the amount of salt in their sweat can vary with the phase of their menstrual cycle. Enough sweat must be
collected to get accurate test results.
Normal values may vary from lab to lab. Sweat chloride must be measured to diagnose cystic fibrosis. Some labs also measure sodium. Normal
and abnormal sweat sodium values vary slightly from sweat chloride values.
Sweat chloride Normal: less than 40 millimoles per liter (mmol/L)
Borderline: 40–60 mmol/L
Abnormal: greater than 60 mmol/L
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Greater-than-normal values may mean
Sweat chloride levels greater than 60 mmol/L are generally diagnostic of cystic fibrosis. Some people with cystic fibrosis have borderline or even
normal sweat chloride levels.
Some other conditions that can cause a higher-than-normal amount of salt in sweat include:
Poorly functioning adrenal glands (adrenal insufficiency or Addison's disease).
Hypothyroidism.
A condition (called diabetes insipidus) that is caused by an inability of the body to maintain normal levels of water.
Kidney failure.
However, the sweat test is never used to diagnose these conditions.
Lower-than-normal values may mean
Decreased sweat chloride levels can result from:
Hypoaldosteronism, a metabolic disorder caused by a deficiency of the hormone aldosterone, which is produced by the adrenal glands.
Sodium loss (such as from excessive sweating or dehydration).
Taking mineralocorticoid medications, such as fludrocortisone (Florinef).
What Affects the Test
It may be difficult to collect enough sweat from an infant to test.
A skin rash or sore on the area of the skin where the gauze pads are attached may cause inaccurate results.
Acute or severe illness can cause either false-normal or abnormal test results.
Hot weather or strenuous exercise before having the test can cause a child who has cystic fibrosis to sweat and lose large amounts of salt, causing
inaccurate results.
A cold room may decrease sweating, affecting the results.
Normal fluctuations in sodium and chloride during puberty can affect the results of a sweat test.
What To Think About
Usually two sweat tests are done to confirm a diagnosis of cystic fibrosis. If a child is found to have cystic fibrosis, the parents may benefit from
genetic counseling.
If results of a sweat test are positive or unclear (especially in infants), a blood test may be done to detect changes in the genetic material (DNA) that
causes cystic fibrosis. Blood test results are usually ready in 10 to 21 days. The blood test results can help predict how severe the condition will be.
A stool sample can also be tested for elastase or trypsin, which are pancreatic enzymes that break down proteins in the intestine. These enzymes
may be lower than normal or absent in people with cystic fibrosis. However, because pancreatic function may be normal in some people with cystic
fibrosis, a stool enzyme test is not as reliable as the sweat test. For more information, see the medical test Stool Analysis.
The degree of sweat chloride elevation does not indicate the severity of cystic fibrosis.
A sweat test cannot identify carriers of the cystic fibrosis gene.
Sweat tests should be done at labs that are certified by the Cystic Fibrosis Foundation. These labs perform a large number of sweat tests and are
skilled at sweat test techniques and interpretation.
Credits
Author Kattie Payne, RN, PhD
Editor Renée Spengler, RN, BSN
Associate Editor Daniel Greer
Primary Medical Reviewer Michael J. Sexton, MD
- Pediatrics
Specialist Medical Reviewer Susanna McColley, MD
- Pediatric Pulmonology
Last Updated August 20, 2003
CP2,Area3/6
The Inheritance of Cystic Fibrosis
24
144
•Cystic fibrosis is caused by mutations in the cystic fibrosis
transmembrane regulator (CFTR) gene. This gene makes a
protein that is involved in chloride transport across the cell
membrane.
•Cystic fibrosis is an autosomal recessive condition, meaning
that an affected individual has a fault in both their copies of the
CFTR gene.
•This slide illustrates the steps through which a mature CFTR
protein is made from the CFTR gene.
•Approximately 1 in 22 individuals of European descent carry a
mutation in the CFTR gene. As they have a second working
copy, they are not affected.
•Mutations may, in theory, lie anywhere in the gene, although
there are a number of common mutations. The most common
mutation is a deletion of 3 base pairs leading to loss of a
phenylalanine amino acid at position 508 (shortened to “Delta
F508”). Approximately 70% of all mutations in the CFTR gene
are this mutation.
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Cystic fibrosis
Cystic fibrosis (CF) is the most common serious genetic
condition in the UK, affecting one person in 2500 of North
European origin. CF mainly affects the lungs where thick
mucus builds up causing repeated infections and breathing
difficulties, and the pancreas where blockages cause digestive
problems. Although doctors can treat the symptoms of CF,
there is no cure at the moment, and the condition is life
threatening by the time the patient is 30 years old.
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The Genetic Code
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Making a Diagnosis
of Marfan Syndrome
Many people are tall and thin, and many have
extensible joints, but only a small number of people
have marfan syndrome. So how do we decide who is
affected ?
The term "syndrome" essentially means a collection
of clinical features that are found together. To have a
diagnosis of Marfan syndrome, a patient must have a
number of different features affecting different
systems (skeletal, eyes, skin cardiovascular and
pulmonary). Essentially it describes a particular
phenotype.
A diagnosis of Marfan syndrome is therefore made on
history and clinical examination and does not
necessarily involve a gene test.
In many patients, Marfan syndrome is caused by
mutations in the fibrillin gene. (See "the genetic
basis of marfan syndrome"). However, when we test
an individual for a mutation, we do not always find
one. This could be because our techniques are not
good enough to detect all mutations, or because the
mutation lies in a different gene. We know about
some of the other genes that can cause a disease
like marfan syndrome, but there are others that we
have not yet identified.
Where we know the fibrillin gene mutation that has
caused Marfan syndrome in the family, we can offer
testing to other family members to see if they also
carry the mutation. It is important to remember that
they may not know that they are affected. In this
situation, doing a test is described as
"presymptomatic testing", and requires careful
genetic counselling in advance of the test.
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Aortic Dissection
Please view footage running on PC
Living with Marfan Syndrome - A Firsthand Account
My name is Julie Whittington and I am a 22-year old
senior at Virginia Tech. I am studying Property
Management and Housing and will be graduating in
December of 2005. I grew up in a small town in
Southside Virginia and love the slower paced life. I stand
at six feet tall even, and might weigh 125 lbs. soaking
wet, so I am very tall and very thin. I have long arms and
I am all legs. My fingers and toes are also long and thin
and my feet are as flat as they come. The reasoning
behind my appearance is because I have Marfan
Syndrome. I would like to tell you what it is like to live
with the disorder and provide an explanation of what
Marfan Syndrome is.
When I was born, they discovered that I had a dislocated hip. I was 23 inches long at birth and did
not have sufficient room in the womb to stretch and this caused my hip to dislocate. I had surgery to
repair the dislocation at six months old, and was placed in a body cast for six months to heal
afterwards. At four, my doctor noticed what he thought to be a heart murmur and I was diagnosed
with Mitral Valve Prolapse (MVP), which is a related disorder but not a characteristic of Marfan
syndrome. The same doctor who found MVP also found evidence of scoliosis and referred me to an
orthopedist. There I was diagnosed with S-curve scoliosis.
With the exception of three to five routine doctors visits a year and not being able to participate in
contact sports; my days consisted of the same activities and events of most of my peers. For as long
as I can remember, I have always had to wear glasses or contacts to correct my nearsightedness.
When I was nine, I went to a routine orthopedist appointment where they discovered my case of
scoliosis was worsening and I was then fitted for a brace to prevent surgery down the road. I wore the
brace for five years until I had my first spinal fusion at age fourteen. A spinal fusion is a procedure
where the surgeon fuses the vertebrae together and holds them in place with steel rods and hooks.
Throughout high school I was able to do everything every
other high schooler could, with the exception of a few
activities. In my junior year of high school I was even able
to take horseback riding lessons, which really helped me
deal with the emotional side affects of having this disorder.
I graduated from high school and spent my last summer
enjoying myself before I went to Blacksburg, Virginia to
attend my freshman year at Virginia Tech. Freshman year
went off without a hitch and I found that people were a lot
more open minded to the appearance of others. The summer
between freshman and sophomore year I started to notice a
great deal of discomfort in my lower back. The discomfort
turned in to severe pain and I went to the doctor to find out
that one of the rods had broken in my back and needed to
be removed. So in October of 2002, I had a partial rod
removal. After the broken rod was removed the pain was
much better, for a little while. I was still having a little bit of
pain and as time went on the pain just got worse.
My mom contacted the National Marfan Foundation to find one of the best doctors. We were given a
list of physicians who were familiar with Marfan, of which we chose Dr. Paul Sponseller at JohnsHopkins in Maryland. After visiting Dr. Sponsellers office we decided that another spinal fusion
would straighten my spine even more than the first one, and could help with the pain. In May of
2004, I had my second spinal fusion. The recovery was a little harder than I expected, but I have been
pain free in my back and I am standing much straighter.
The next thing that needed to be addressed was my inverted breast bone. Dr. Sponseller referred us to
a doctor in Norfolk by the name of Dr. Nuss. I went to see him about four months after my surgery.
Dr. Nuss told me what I already knew. I needed surgery. When determining if patients need surgery,
measurements are taken of the deformity and a ratio is created. Doctors consider a 3 to be severe
enough to have surgery. I was an eight. So in November of 2004 at twenty one, I had the fifth surgery
of my life. This one has proved to be the most difficult to overcome because I am still a work in
progress and the surgery was more extensive than it normally is. It also did not help that I had two
major surgeries in six months time. Even though I am still recovering, I am back at school trying to
finish up and graduate so that I can move on and start working on fulfilling my dreams.
I don’t write this long explanation of my medical ailments to get sympathy. I write it because I want
people to be more aware of Marfan syndrome. I have also dealt with the emotional side affects of
having this disorder, which is what I think is the hardest part of living with Marfan. So if I can help
someone who has Marfan syndrome feel like there is someone else out there who knows how they
feel and help them feel better about themselves, then my mission is complete. Growing up differently
than other kids is not an easy task. Sure everyone gets teased about something when they are a kid,
but its so much easier to pick on someone that is so different from yourself. There were a few kids
who terrorized me as a kid, and stares and pointing of people in public really allows for a low selfesteem.
You also think “why me?” and wonder what you have
done to deserve all of this. It’s also scary to go through
surgery. All these things can take a toll on your emotions
and it can do one of two things. It can either break your
spirit or make you a stronger person. You have to
remember that if someone can’t accept you for who you
are, then they aren’t worth knowing. As you age, I find
that people are more accepting of the way you look and
they do not really care about the exterior as much as the
interior. I know I am like this for a reason and luckily, I
have a great family and a strong support system of friends,
family, and my church family that help me get thru every
obstacle. These hurdles that I have overcome have only
made me a stronger, more caring, and compassionate
person. I know I look different than most girls my age, and
sometimes it’s hard to deal with because you just want to
blend in with the rest. I am different and I have many
things to bring to the table.
I have told my story and would not want any part of it to be different. These experiences and
challenges have made me who I am today. Just remember, before you judge or point, that person has
a story to tell, a great one. And if you are the one they are pointing at, just hold your head high and
remember that they haven’t heard your story yet.
What You’re Supporting
Marfan Syndrome is a genetic disorder that affects the connective tissue in people of all ages, races,
and genders. One in five thousand people have the disorder and there is a fifty percent chance for a
parent with the disorder to pass it on to the child. The disorder can affect multiple systems of the
body which include the skeletal, nervous, ocular (eyes and sight), cardiovascular, and pulmonary
systems. Marfan Syndrome was defined by Antione Marfan, a French physician, who examined a
patient who had long and thin fingers, toes, arms, and legs, as well as a curvature of the spine
(scoliosis), and poor muscle definition.
Characteristics of the Disorder
Note that not all characteristics are present in everyone with Marfan Syndrome.
• Skeletal
•
•
•
•
•
•
Toes, fingers, legs, and arms are disproportionately long
Double-jointedness, or “loose joints”
Flat feet
Concave or convex breastbone
Curvature of spine (Scoliosis)
Very tall or taller than most other members in the family
•
•
•
•
Dislocated lenses in one or both eyes
Glaucoma
Cataracts
Nearsightedness
•
•
•
Dilation or tearing of the Aorta
Heart murmur caused by leakage in the valve between the left chambers of the heart
Severe cases can cause palpitations, shortness of breath and fatigue.
•
Dura (spinal fluid in a membrane surrounding the brain and spinal cord) is weakened
and stretches with age
This can cause mild discomfort in the lower back, as well as compression of the
vertebrae
Compression can cause abdominal pain and pain, weakness, and numbness in the
legs
• Ocular (Sight and Eyes)
• Cardiovascular (Heart and Blood Vessels)
• Nervous
•
•
• Pulmonary
•
•
Lungs are less elastic
Sleep apnea or snoring
•
•
Stretch marks can occur without weight change or pregnancy
Abdominal or groin hernias can occur
• Skin
Diagnosis
When doctors diagnose the patient with Marfan Syndrome, they look for the above characteristics.
They also perform an echocardiogram to look at the heart and valves, exam the eye with a “slit lamp”
to view any abnormalities, and perform a physical evaluation. The evaluation is done to asses the
skeleton and figures the ratio between arm/ leg and trunk length, and look for abnormal bone
changes.
Marfan Syndrome
Marfan syndrome is a disorder of connective tissue. It is inherited as an autosomal dominant
condition and affects up to 1 in 10,000 in the general population. Marfan syndrome shows very
variable expressivity - affected individuals may be mildly or severely affected even within the same
family. It is a condition that affects many different body systems.
Genetic basis of Marfan Syndrome
In many cases, marfan syndrome is caused by a mutation in the fibrillin gene, which is found on
chromosome 15. This mutation may lie anywhere in the gene. Some mutations casuse a
premature termination of the protein, others will change an important amino acid or prevent normal
splicing of the pre-mRNA into mRNA. Fibrillin is an important component of connective tissue which
makes up blood vessels and joint ligaments. Fibrillin also plays a role in signalling by a cytokine
called TGF-beta.
An affected individual carries one working and one faulty copy of the gene. It is therefore inherited
as an autosomal dominant condition. This is illustarted below. As you pass on one of each
chromosome, and therefore one copy of each gene, to a child, there is a half chance that a child
would inherit the gene change. However, expressivity of the condition is very variable. The child
who inherits the mutation may be severely or mildly affected.
Marfan Syndrome can affect many different systems
Skeletal features
Individuals with marfan syndrome can have multiple skeletal features, including:
Long arms and legs
Long fingers (arachnodactyly)
Hyperextensible joints
Chest deformity (pectus excavatum or carinatum)
Curvature of the spine (scoliosis)
High arched palate
Characteristic facial features
Skeletal features of Marfan Syndrome
"Thumb sign" positive. This patient's thumb can be pushed through their closed fist with the distal
phalanx protruding. This demonstrates both hyperextensibility and arachnodactyly.
Severe scoliosis in an affected patient
Typical facial features seen in a proband
Eyes
Myopia (short sight)
A proportion of patients with Marfan syndrome have dislocated lenses
Heart and Cardiovascular system
These are the most worrying features of Marfan Syndrome. Affected individuals can have:
Mitral valve prolapse
Dilatation and rupture of the aortic root and ascending aorta
Echocardiogram Showing Dilatation of the Aortic Root (Ao) with prolapse of the mitral valve (mvp)
X-ray showing a widely dilated aortic root (marked with arrow).
Other Systems
Marfan syndrome can also cause pneumothorax, striae on the skin and dural ectasia
PSYCHOSOCIAL PRINCIPLES
The case scenarios you have been given for this week’s ITA sessions all highlight aspects of the genetic basis of disease. As well
as understanding the technicalities, it is also important that you
know how having a genetically linked condition affects the patients,
and those who live with, love, and care for them.
Scenario 1
Many conditions have specific risk factors associated with them,
and it is possible, and often necessary, to advise patients on ways
to change these. However, you need to be able to recognise which
factors the patient can actually do something about!
Scenario 2
You are encouraged to think about how disease trends (such as the
change in the incidence of a particular condition) may be linked to
other factors which are not concerned primarily with clinical diagnosis or management.
Scenarios 3 and 4
Look at the scenarios from the viewpoint of the patients and their
families, and explore some of the ways in which chronic illness can
affect family relationships.
Scenario 1
From the history Arthur Jones has given, his family has a clear record of heart
problems, and Arthur is now suffering himself. There are a number of factors
which may have conspired to place Arthur in the situation he is in.
When we talk about this in the context of illness, we use the term risk. In this
case, we would say that Arthur is at greater risk of heart disease for a variety of
reasons. These reasons are known as risk factors. In general, these risk factors
are divided into two types, Modifiable and Non-modifiable risk factors; however,
there can be some grey areas in between!
Below are some risk factor types. Which of these are Modifiable and which Nonmodifiable? Are there any which you find hard to classify? Consider how you
might use this system to improve your understanding of Arthur’s case
Genetic Factors
Mental & Physical
fitness
Age
Sex
Lifestyle
Nutritional status
Co-morbidity
(suffering from other
diseases at the same time)
Personality &
mental disposition
Scenario 2
Marie has been told that she has Sickle Cell Disease. This condition does not occur in the same numbers in all populations. The number of cases in the UK has
risen steadily since records began.
Read the extract below, and look at the distribution map.
Consider why you think the numbers may have increased. Consider whether you
think this increase in numbers indicates that the disease is getting more serious,
or whether it might reflect some other underlying trend.
“Sickle cell anemia affects millions throughout the world. It is particularly
common among people whose ancestors come from sub-Saharan Africa;
Spanish-speaking regions (South America, Cuba, Central America); Saudi
Arabia; India; and Mediterranean countries such as Turkey, Greece, and
Italy. In the United States, it affects around 72,000 people, most of whose
ancestors come from Africa. The disease occurs in about 1 in every 500 African-American births and 1 in every 1000 to 1400 Hispanic-American
births. About 2 million Americans, or 1 in 12 African Americans, carry the
sickle cell trait.”
Text from the US information site on the Human Genome Project:
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/sca.shtm
Source: WHO
Scenarios 3 and 4
Both Fred’s and Ian’s cases give the opportunity to think about how these men’s
illnesses may have affected the other members of their families.
Ian’s mother and father will have had to care for him since he first became ill as a
child; his sister will have experienced growing up with a brother who was often ill,
and may not have been able to take part in play and other activities like her other
friends and their siblings. In addition, Claire may be very worried about the future for
her child if it develops cystic fibrosis – she has already seen what it is like for her
parents learning to live with a child with the disease.
In Fred’s case, he already has 2 sons – what about his concerns for them, and their
own concerns for the future? Will they need to care for their father as he gets older?
How will the diagnosis impact upon their own future plans for families?
Read the following extract and then consider how you think the concepts it outlines
could apply to both of these case scenarios.
“Illness in the family causes a major disruption altering how families relate
and may ultimately impede their ability to overcome the ramifications of the
illness experience. Illness may demand a change in the family role structure
and task allocation. Changes in routine may be required, such as childcare
responsibilities or visits to the hospital. Major alterations may be needed,
such as substantial home renovations to accommodate a wheelchair-bound
family member or a return to the workforce to provide for the financial needs
of the family.
The disequilibrium in the family resulting from illness can also alter the established rules and expectations of the family, transform their methods of communication and substantially alter the family structure. For example, after the
diagnosis of terminal breast cancer, a mother transferred her responsibilities
for the care of her five children to her eldest daughter, aged 16. The daughter,
in turn, quit school, assumed the full caretaker role for her siblings and became her father’s confidante as he watched his wife resign herself to her
cancer. The changes imposed on families by illness are limitless and are
accompanied by a host of feelings – loss, fear, anger, resignation, anxiety,
sadness, resentment and dependency.”
From Patient-Centered Medicine, Eds Stewart et al, second edition, 2003,
Radcliffe, Abingdon UK. Page 65.