Birth Defects was written for healthcare workers who look after individuals with birth defects, their families, and women who are at increased risk of giving birth to an infant with a birth defect. This book is being used in the Genetics Education Programme which trains healthcare workers in genetic counselling in South Africa. It covers: modes of inheritance, medical genetic counselling, birth defects due to chromosomal abnormalities, single gene defects, teratogens, multifactorial inheritance

1. 4
Single gene
disorders
Before you begin this unit, please take the INTRODUCTION TO SINGLE
corresponding test at the end of the book to
assess your knowledge of the subject matter. You GENE DISORDERS
should redo the test after you’ve worked through
the unit, to evaluate what you have learned.
4.1 What is a single gene defect?
This is an abnormality (mutation) in a single
Objectives gene which results in a genetic disorder
(birth defect). Single gene defects cause
many structural and functional (biochemical
When you have completed this unit you
or metabolic) birth defects. The number of
should be able to: chromosomes is normal with a single gene
• Define a single gene disorder. defect.
• Describe Waardenburg syndrome,
A single gene defect may be inherited in a
oculocutaneous albinism, and number of different patterns:
haemophilia.
1. Autosomal dominant, e.g. Waardenburg
• Explain how these conditions are
syndrome.
inherited. 2. Autosomal recessive, e.g. oculocutaneous
• Recognise the clinical features of a albinism.
person with any of these conditions. 3. X-linked recessive, e.g. haemophilia.
• List the clinical complications of these In addition, a single gene defect may be due
conditions. to a new mutation (autosomal dominant or
• Plan the care of a person with these X-linked recessive). With a new mutation
conditions. affected individuals will not have a family
• Explain how these conditions can be history of that condition.
diagnosed prenatally.
Single gene defects cause clinical conditions
resulting from mutations in a single gene.

2. SINGLE GENE DISORDERS 67
Waardenburg syndrome, oculocutaneous 4-4 How common is
albinism and haemophilia are typical examples Waardenburg syndrome?
of disorders due to single gene defects
Waardenburg syndrome is rare. It occurs in
with different patterns of inheritance. They
about 1 in 30 000 people in all populations.
illustrate many of the problems and principles
of care and management for people with single In southern Africa approximately 4% of people
gene defects, and their families. with profound deafness have Waardenburg
syndrome. This is similar to studies from other
parts of the world where the prevalence of
WAARDENBURG Waardenburg syndrome amongst deaf people
varies from 2 to 5%.
SYNDROME
4-5 What are the main clinical features of
4-2 What is Waardenburg syndrome? people with Waardenburg syndrome?
Waardenburg syndrome is an inherited The main clinical features of Waardenburg
disorder that is made up of a recognisable syndrome are:
collection of clinical features including 1. Very blue eyes (sapphire blue). The iris of
deafness. It is the commonest cause of both eyes can have this extraordinary blue
inherited deafness associated with a known colouring which is very noticeable in black
syndrome in southern Africa. Africans who usually have brown eyes. In
some cases only one eye or part of the iris
4-3 How is Waardenburg has this colouring and the other eye or
syndrome inherited? part of the iris has the normal eye colour
(heterochromia).
Waardenburg syndrome is an autosomal
2. Some people with Waardenburg syndrome
dominant disorder:
have abnormal tear ducts. This can cause
1. About two thirds of individuals with repeated eye infections.
Waardenburg syndrome have inherited the 3. Eyebrows. The inner (medial) part of
abnormal dominant gene, and therefore the the eyebrow is very bushy and often the
clinical condition, from an affected parent. eyebrows meet in the middle (synophoris).
2. The remaining third of people with 4. Deafness. Sensory (nerve) deafness is
Waardenburg syndrome have the condition the most serious feature of Waardenburg
as the result of a new gene mutation. syndrome. It usually involves both ears and
Therefore their parents are normal and is severe. Deafness is found in 25 to 50% of
neither has the abnormal gene. people with Waardenburg syndrome.
5. A white forelock. Between 30 and 40% of
NOTE The new gene mutation for
people with Waardenburg syndrome have
Waardenburg syndrome is associated with
a white or grey patch of hair in the middle
advanced paternal age (having a father
older than 50 years) at the time of birth. and front of their heads. This may vary
from a small area that is not very obvious
to a large striking white forelock of hair.
Waardenburg syndrome is inherited as an 6. Early greying of hair and eyebrows. This
autosmal dominant disorder. begins in the twenties in some people with
Waardenburg syndrome.
7. Partial albinism. About 20% of people with
Waardenburg syndrome have patches of
skin with less or no pigmentation.

3. 68 BIR TH DEFECTS
2. Recurrent eye infections (conjunctivitis)
Individuals with Waardenburg syndrome can be
in infants and children caused by the
deaf and have a characteristic white forelock.
problems with the tear ducts.
NOTE There are considered to be two main
forms of Waardenburg syndrome, types I and II, 4-9 Are people with Waardenburg
both of which have similar features but which syndrome intellectually disabled?
can be told apart because type I has dystopia No. However, infants and children with
canthorum and type II does not. Dystopia
deafness from any cause, including
canthorum is the name given to the facial
feature in which the inner corners (canthi) of
Waardenburg syndrome, are often considered
each eye are further apart than normal and the to be developmentally delayed. This is
nasal bridge is broad. Careful examination of the because of the lack of speech and inability to
lower eyelid will also show that the openings communicate. If the problem is discovered
to the tear ducts (lacrimal puncta) are further early and appropriate speech therapy started,
away from the inner corners of the eye than many of the developmental problems may be
usual. People with Waardenburg syndrome overcome and the person is shown to have
type II do not have these features. Deafness is normal intelligence.
found in 25% of people with type I and 50% of
people with type II Waardenburg syndrome.
In southern Africa, type I is the commonest 4-10 What care is available for people
(over 50%) form of Waardenburg syndrome. with Waardenburg syndrome?
1. Early diagnosis:
4-6 Must a person have all these In people with Waardenburg syndrome,
features to be diagnosed with as with all cases of infant and childhood
Waardenburg syndrome? deafness, it is very important to diagnose
No. Three or more of the main features their deafness as early as possible
must be present to consider the clinical to ensure they can start early with
diagnosis. In Waardenburg syndrome, as is intervention programmes. This will
found in many other syndromes, the number ensure the best long-term outcome for the
and severity of the clinical features present person’s communication ability. The early
can vary greatly. This is called variation in clinical confirmation of the diagnosis of
expression of the syndrome (i.e. not all the Waardenburg syndrome is also important
features are expressed). so that genetic counselling can be offered
to the family.
2. Managing the deafness:
4-7 Is there a test to confirm the
The early diagnosis of deafness, in infancy
diagnosis of Waardenburg syndrome?
if possible, is important so speech and
Yes. The gene for Waardenburg syndrome communication therapy can be started
can be identified to confirm the diagnosis. early ensuring the best long-term results.
However, the test is expensive and currently Assessment to decide if hearing aids may
not undertaken in South Africa. benefit the infant or child should also be
done as early as possible. Assessment and
4-8 What are the major complications initial speech therapy need to be done at
of Waardenburg syndrome? a specialised centre. On-going day-to-
day speech therapy in areas far from such
1. Deafness and the problems associated centres may be made possible for infants
with this, including lack of speech and and young children with the help of
communication ability, schooling problems community-based rehabilitation workers.
and social stigmatisation. However, to achieve the best results, these
children will need to regularly attend

4. SINGLE GENE DISORDERS 69
centres for specialised on-going assessment 4-12 What is the risk for parents of a child
and therapy and eventually need to go to with Waardenburg syndrome having
schools for the auditory disabled (deaf). affected children in future pregnancies?
3. Manage repeated eye infections:
To assess this risk, the parents have to be
Conjunctivitis needs to be treated with
examined to see if one of them has signs of
repeated swabbing of the eye with clean
Waardenburg syndrome. Because of variation
water (boiled and then cooled), massaging
of expression of the syndrome it may not
the tear duct, and antibiotic drops or
have been diagnosed in one of them, as their
ointment if indicated. If the problem recurs
symptoms and signs may not be as severe or
often then surgical probing of the tear duct
numerous as in their child. For example, an
can be performed.
affected parent may not necessarily be deaf.
4. Genetic counselling and psychosocial
support. If a parent is diagnosed with Waardenburg
syndrome, then all future children of that
4-11 What genetic counselling is parent have a 1 in 2 (50%) risk of having
needed by parents who have a child Waardenburg syndrome. These children with
with Waardenburg syndrome? Waardenburg syndrome, when they have
grown up and have their own children, will
Genetic counselling is a major part of the care also have a 1 in 2 (50%) risk of passing the
of people with Waardenburg syndrome and syndrome to each of their offspring. This is
their family, especially the parents. The parents typical of an autosomal recessive disorder.
need to be educated and informed about:
If both parents of a child with Waardenburg
1. The diagnosis. syndrome are normal, then the cause of
2. The cause of Waardenburg syndrome. Waardenburg syndrome in the child is due to
That Waardenburg syndrome is a genetic a new mutation. Future children of that couple
disorder, inherited in an autosomal will have only a very small risk of being affected
dominant manner. However, in a third of with Waardenburg syndrome. But the affected
patients it may occur for the first time in a child will have a 1 in 2 (50%) risk of having an
family as a new mutation. affected child when he or she becomes a parent.
3. What Waardenburg syndrome means for
the affected person and what can be done
4-13 Can Waardenburg
to treat the various problems.
syndrome be prevented?
4. The risks for parents with a child with
Waardenburg syndrome having a child Yes. Because the genes for Waardenburg
with Waardenburg syndrome in future syndrome are known, it is possible to do
pregnancies and their options for reducing prenatal diagnosis. However, as the test is not
this risk and preventing the birth of currently offered in South Africa, prenatal
another affected child. diagnosis of Waardenburg syndrome is not
practical.
The parents, family and child with
Waardenburg syndrome need to be offered
on-going psychosocial support as with all
individuals who have a congenital disability. OCULOCUTANEOUS
There is currently no support group for ALBINISM
Waardenburg syndrome in South Africa.
4-14 What is albinism?
Albinism is an inherited condition. The
clinical signs and symptoms of albinism are

5. 70 BIR TH DEFECTS
caused by a lack of melanin in the cells of the 4-17 How common is
body. Melanin is the pigment that gives colour oculocutaneous albinism?
to the skin, hair and eyes.
Oculocutaneous albinism is the commonest
NOTE Albinism occurs in many animals
single gene disorder in South Africa. The
such as the white lions of Timbavati. population prevalence of OCA in the Black
population is 1 in 4000. However, it is even
higher in those communities that accept
4-15 Are there different types of albinism?
intermarriage (consanguinity) as part of their
Yes, there are different forms of albinism: culture (e.g. the Venda, Tswana, Pedi and
1. Albinism with a lack of pigment in the eye Southern Sotho peoples). The population
(oculo-) plus skin (cutaneous) and hair. This prevalence of OCA in other ethnic groups in
is called oculocutaneous albinism or OCA. South Africa is not known.
2. Albinism which only affects the eyes and
NOTE The population prevalence of OCA is similar
not the skin or hair. This is called ocular throughout most of sub-Saharan Africa, varying
albinism. between 1 in 4000 to 5000 people. The highest
prevalence, 1 in 1000, is found in the isolated
Batonka people who live in the Zambezi River
Oculocutaneous albinism is the result of a lack of valley. In contrast, in Europe, the prevalence of
pigment in the eyes, skin and hair. OCA varies between 1 in 10 000 and 20 000.
NOTE Oculocutaneous albinism is further classified
into types I and II. In sub-Saharan Africa, including Oculocutaneous albinism is the commonest
South Africa, oculocutaneous albinism type II single gene disorder in South Africa.
is the most common form of albinism found.
4-18 What are the main clinical features
4-16 How is oculocutaneous of oculocutaneous albinism?
albinism inherited?
People affected with OCA have normal
OCA is inherited as an autosomal recessive physical and facial features, but have markedly
condition. Therefore, a person affected with decreased pigmentation of their skin, hair and
OCA has received two copies of the abnormal eyes resulting in all these features being pale.
gene (homozygous) that is responsible for Black people with OCA are, therefore, easily
melanin production (i.e. one abnormal gene recognised. In White people, OCA is less
from each parent). As a result, the cells of obvious. The features of OCA are:
an affected individual are unable to produce
normal amounts of pigment and, therefore, 1. Skin
they are very pale. They have pale skin which is very sensitive
to sunlight.
Each parent of an affected individual has one
normal and one abnormal copy of the pigment NOTE They may have small spidery pigmented
gene (i.e. is heterozygous). Because they have patches called ephilides scattered over
one normal gene that can produce melanin, their bodies, mainly on sun-exposed
they have normal pigmentation and do not areas such as the arms and faces.
show signs of OCA. 2. Hair
A black African with OCA usually has pale
or corn-coloured hair. The hair colour in a
Oculocutaneous albinism is inherited as an
few individuals may be brown or reddish
autosomal recessive disorder. (rufous).

6. SINGLE GENE DISORDERS 71
3. Eyes does not take precautions to protect
Black African people with OCA have themselves from the sun. People living
brown eyes, but their eyes may be lighter nearer the equator, where the sunlight
brown than normal. They have numerous is stronger, are at a higher risk.
eye problems. • Early death from skin cancer is a
serious risk for people with OCA.
4-19 What eye problems are common in 2. Eyes
people with oculocutaneous albinism? • Lack of pigment in the eyes can result
in sunlight-induced damage to the eyes.
1. Photophobia. Sensitivity to bright light and This will cause a further worsening in
glare. visual ability.
2. They all have nystagmus. This is jerky • As individuals with OCA have
movements of the eyes in a horizontal or abnormal eyesight, they may
vertical direction or both. experience school learning difficulties
3. Most have poor vision (96%). About two- and job discrimination in later life.
thirds are short sighted (myopia) and a 3. Social stigmatisation
third long sighted (hyperopia). • People with OCA in Africa look
very different from the rest of the
All people with oculocutaneous albinism have population.
problems with their eyesight. • Throughout Africa, myths or legends
regarding the birth, life and death of
NOTE Most people with OCA have astigmatism
people with OCA are common. These
(92%) and poor depth judgement. They also myths can affect people’s attitudes to
have abnormal visual pathways as the gene people with OCA, mostly negatively
for melanin production is responsible for the but in some populations positively.
development of the optic nerve tracks from the Therefore, in many regions of sub-
eye to the visual centre at the back of the brain. Saharan Africa there is isolation and
Because of their abnormal visual pathways they stigmatisation of people with OCA.
do not have binocular vision like normal people.
Research from South Africa indicates that
people with OCA are now generally well
4-20 What are the major complications
accepted in the community, and they in turn
of oculocutaneous albinism?
appear to be reasonably well adjusted. Myths
1. Skin regarding people with OCA are, however,
Normally, melanin prevents the sun’s plentiful, and it has been reported that
ultraviolet rays being absorbed by the mothers of newborns with OCA experience
skin. If melanin is not present in adequate problems bonding with their infants and
amounts, the ultraviolet rays in sunlight may suffer from depression, similar to that
penetrate and damage the skin. Problems described by mothers with other birth defects.
resulting from a lack of pigmentation in
the skin include:
• Easy sun-burning and blistering. Skin cancer is a common complication of
• Rapid ageing of the skin which leaves oculocutaneous albinism.
it thin, dry and it is easily damaged.
These areas of skin often become 4-21 What are some of the South
infected. African myths regarding people
• Skin cancer (squamous cell carcinoma). with oculocutaneous albinism?
People with OCA are at high risk of
developing cancer of the skin on sun- 1. Birth myths:
exposed areas, especially if the person

7. 72 BIR TH DEFECTS
These are used to try and explain the 30 years. No figures on life expectancy are
unexpected birth of an infant with OCA. currently available for South Africa. However,
They include that the birth is a punishment it is considered to be better than the figure for
for some supposed bad deed committed by Tanzania and Nigeria as South Africa is mostly
the parent(s); that the mother conceived outside of the tropics.
during menstruation; that the mother
must have come into contact with a person
with albinism during pregnancy; that the
Many people with oculocutaneous albinism die
mother ate an excess of certain foods or of skin cancer.
had an infection during pregnancy.
2. Life myths: 4-24 What is the correct care for people
These are about special qualities that with oculocutaneous albinism?
people with OCA supposedly have. One
1. Early clinical diagnosis:
of the common beliefs is that people with
The first step in caring for people with
OCA may have special religious, spiritual
OCA is to make an early, correct diagnosis.
or supernatural power. People with OCA
OCA is a clinical diagnosis and is usually
are often considered either very intelligent
made at the birth of the infant, especially
or intellectually disabled.
in the black African infants in whom
3. Death myths:
the diagnosis is very obvious. However,
The death of people with OCA is
the clinical signs can be more difficult to
surrounded with superstition. It is widely
recognise in White or Asian infants.
believed that they do not die, but rather
2. Good skin and eye care:
disappear or vanish.
Good skin and eye care is essential to
prevent skin cancer and progressive loss
4-22 Are children with oculocutaneous of eyesight.
albinism intellectually disabled? 3. Neurodevelopmental therapy, special
No. Children with OCA generally have a education and rehabilitation:
normal intelligence and are not intellectually This should be provided in the community,
disabled. Due to their visual disability, infants if possible, to enable these children to learn
and young children may present with evidence and develop normally.
of developmental delay. Older children may 4. Genetic counselling and psychosocial
have schooling problems due to their poor support.
vision or psychosocial problems. However,
if these problems are recognised early and 4-25 What skin care is needed for children
correctly treated with eye and visual care, early with oculocutaneous albinism?
intervention programmes and counselling,
It is essential for people with OCA to reduce
they can be overcome.
their exposure to sunlight to the greatest extent
possible. As it is not possible for a person with
4-23 What is the life expectancy of OCA to remain out of the sun continually,
children with oculocutaneous albinism? when they do go outdoors they should wear
The life expectancy of people with OCA clothes to cover as much skin as possible, i.e.
should be similar to that of normal people. long trousers or skirts, long-sleeved tops or
However, due to the high risk of developing shirts, and hats with wide brims.
skin cancer, many unfortunately die in Sun-exposed skin, especially hands, arms and
early adult life if not correctly treated and face, should be covered with cream containing
counselled. In Tanzania and Nigeria, countries sunscreen (sun barrier creams). Cream with
in the tropics and close to the equator, only sun protection factor (SPF) of 30 or greater
10% of people with OCA live longer than

8. SINGLE GENE DISORDERS 73
must be used. Moisturising cream should be receive neurodevelopmental therapy, e.g.
used on dry, cracking or chaffed skin, and skin occupational therapy at their local hospital.
infection should be treated vigorously with 2. If specialised therapy is not available in
antiseptics and antibiotics if clinically indicated. their area they will have to rely on local
Unfortunately many clinics do not have sun community-based rehabilitation services.
barrier creams. They are expensive to buy. 3. When children with OCA reach school-
going age, decisions will need to be made
Adolescents and adults with OCA should
regarding school placement. Where
be aware of the dangers of skin cancer. They
possible, children with OCA should be
should be taught how to recognise areas of skin
encouraged to attend normal schools.
cancer so that they know what to look for to be
Efforts to assist them in a normal school
able to suspect and possibly diagnose cancer as
may be necessary, e.g. placement in the
early as possible (e.g. sores that do not heal). In
front row of the class. If, however, their
addition they should have yearly examinations
visual disability is too severe, then scholars
to exclude the development of skin cancer.
may need to be placed in a school for the
visually disabled.
Good skin protection against sunlight is essential
to prevent skin cancer. 4-28 What genetic counselling is needed
for families with oculocutaneous albinism?
4-26 What eye care is needed for children Genetic counselling is a major part of the
with oculocutaneous albinism? care of people with OCA and their family,
People with OCA need to protect their eyes especially their parents. The parents need to be
from the harmful effects of sun and bright educated and informed about:
light by avoiding it where possible and 1. The diagnosis, which is a clinical one and is
wearing protective eyewear (appropriate dark usually obvious.
glasses with an ultraviolet screen) and broad- 2. The cause of OCA. To explain that
brimmed hats. In this way, further damage to OCA is a genetic disorder, inherited in
their visual disability can be minimised. an autosomal recessive manner. This
All people with OCA should have regular information can be used to try and dismiss
ophthalmic or optometric assessments from the myths about why an infant with OCA
infancy. This is necessary to ensure they is born to a couple.
obtain the correct glasses and treatment for 3. What OCA means for the affected person,
their individual problems. This gives them what can be done to prevent and manage
the best chance of reasonable vision and the various problems. It is essential to stress
ensures that their sight is not damaged by the that every effort must be made to avoid
lack of eye care. direct sunlight on the skin and in the eyes
by not spending a lot of time in the sun,
wearing the proper clothes and protective
Good eye care, protection from the sun, and the eyewear and using sunscreen cream.
correct glasses are essential to protect eye sight. 4. The risks for normal parents with an OCA
infant having another child with OCA
in future pregnancies. Their options for
4-27 What neurodevelopmental therapy,
reducing the risk of having another infant
community-based rehabilitation and
with OCA should be discussed.
special education are needed for children
with oculocutaneous albinism? The parents, family and person with OCA need
to be offered on-going psychosocial support.
1. In infants and children with severe visual
disability it may be necessary for them to

9. 74 BIR TH DEFECTS
4-29 What is the risk for normal 4-32 Who can offer psychosocial support?
parents of a child with oculocutaneous
Professional psychosocial support can be
albinism having other affected
obtained from:
children in future pregnancies?
1. Doctors, nurses (especially nurses with
OCA is an autosomal recessive condition.
postgraduate genetic training), genetic
As carriers of a single abnormal OCA gene,
counsellors and neurodevelopmental
parents of a child with OCA have a 1 in 4 risk
therapists.
(25%) of having a further affected child in
2. Social workers.
every future pregnancy. With another partner,
3. Patient/parent support groups. These
the chance of either parent having an affected
groups play a vital role in offering
child is very small.
information and support to people affected
with congenital disability.
4-30 How can oculocutaneous
albinism be prevented? There is a strong support group for people
with OCA in South Africa, the Albinism
The gene for OCA has been identified and, Society of South Africa (ASSA), P O Box 9881,
therefore, it is possible to offer prenatal Johannesburg, 2000. (Tel: 011- 838-629)
diagnosis for OCA to parents who both carry
the abnormal gene. This can only be done
after the parents receive genetic counselling.
Genetic counselling is ideally undertaken
HAEMOPHILIA
before conception, or in the first 10 weeks of
the pregnancy. The prenatal gene test is done 4-33 What is haemophilia?
on fetal cells obtained by amniocentesis at 16
weeks. Once the result of the prenatal test is Haemophilia is an inherited, lifelong bleeding
available, further genetic counselling will be disorder which affects mainly males.
necessary to discuss these results. There are two types of haemophilia,
haemophilia A and haemophilia B.
4-31 Why do people with Haemophilia A (classical haemophilia) is the
oculocutaneous albinism, and their common form of haemophilia. Both types
family, need psychosocial support? present clinically as a bleeding problem.
People with OCA, as with all individuals who
have a congenital disability, suffer lifelong 4-34 Why do patients with
problems which require lifelong care. The haemophilia bleed excessively?
burden of the disorder is experienced not Haemophilia A is caused by a lack of normal
only by the affected person, but also the functioning clotting factor VIII (eight) while
family, especially parents, brothers and haemophilia B is caused by a lack of normally
sisters. Mothers of newborns with OCA need functioning clotting factor IX (nine).
psychosocial support to help them accept and
bond with their infant, and overcome possible NOTE It is the low level of function, rather than
depression. In addition, the problem is a low concentration of the clotting factor
genetic and thus there is the possibility for the in the blood, which results in an increased
parents, the affected person and other family tendency to bleed. The single gene defect
members to also have children affected with results in the formation of a defective clotting
factor, which does not function normally.
OCA. Support, help and reassurance in these
circumstances may be a lifelong need.
Haemophilia is a bleeding disorder due to the
lack of a normal clotting factor.

10. SINGLE GENE DISORDERS 75
4-35 How is haemophilia inherited? care in many black communities, some
black people with haemophilia A may not
Both types of haemophilia are inherited as X-
be diagnosed and registered. Others may
linked recessive disorders. There are different
die very young with severe bleeding without
single gene defects on the X chromosome for
the diagnosis being made. Therefore the
haemophilia A and haemophilia B on the X
population prevalence is less than expected.
chromosome.
A woman with a haemophilia gene (i.e. an 4-38 What are the main clinical features
abnormal gene) on only one X chromosome of people with haemophilia?
is a carrier (i.e. she is a heterozygote).
Because she has a normal gene on her other X People with haemophilia present with
chromosome, she will still be able to produce excessive bleeding. The bleeding may be in
enough clotting factor. If she passes the X the skin and mucous membranes (bruising),
chromosome containing the abnormal gene muscle, joints, internal organs or brain. Infants
on to her daughter, then her daughter will usually bleed into soft tissues while older boys
also be a carrier. usually bleed into joints.
If a son inherits the X chromosome with the The severity and frequency of bleeds depends
haemophilia gene from his mother, he will have on the concentration of clotting factors VIII
haemophilia as his short Y chromosome does and IX in the patient’s blood:
not have the gene to produce the clotting factor. 1. People with mild haemophilia only have
5 to 35% of the normal factor VIII or IX
Haemophilia is inherited as an X-linked recessive level. They usually only bleed following
severe trauma and at surgery. Because
condition. Women carry the abnormal gene
bleeding is not a major problem they may
and their sons are at 50% risk of inheriting only be diagnosed later in life.
haemophilia. 2. People with moderate haemophilia have
between 1 and 5% of the normal factor
4-36 Can females have haemophilia? VIII or IX level and they bruise easily.
They usually bleed excessively following
Yes. About 10% of female carriers have signs of trauma, surgery or dental care but rarely
mild haemophilia. All patients with moderate have spontaneous bleeds. They usually do
or severe haemophilia are males. not have serious problems with bleeding
into joints. Diagnosis before the age of five
NOTE If a daughter inherits a haemophilia gene
from her carrier mother and another from her years is possible.
haemophiliac father, both her X chromosomes 3. People with severe haemophilia have less
will contain the abnormal gene and she than 1% of the normal factor VIII or IX
will have haemophilia. This is very rare. level and may bleed spontaneously or with
minimal trauma. They can bleed in any part
4-37 How common is haemophilia? of the body but some parts such as the large
joints (knees, ankle and elbow) are more
1. Haemophilia A occurs in approximately 1 at risk of injury and bleeding. Diagnosis
in 5000 males throughout the world. should occur in the first year of life.
2. Haemophilia B occurs in approximately 1
in 40 000 males throughout the world. Bleeding is unusual in newborns but infants
with haemophilia can bleed from circumcision
In South Africa, haemophilia A has been found sites. Infants with severe haemophilia will bleed
in 1 in 5000 white males but only 1 in 20 000 into muscles from injection or needle-stick sites
black males. Due to poor socioeconomic or spontaneously into cephalhaematomas or
conditions and inadequate access to health within the skull (intracranial bleed).

11. 76 BIR TH DEFECTS
4-39 Are there tests to confirm the causes in the joint. Arthritis can develop.
diagnosis of haemophilia? Physical disability resulting from joint
damage is a major problem for people with
Yes. If haemophilia is suspected, the following
haemophilia in developing countries.
tests can be done to confirm the diagnosis:
2. Muscle and soft tissues
1. Partial thromboplastin time (PTT). This Bleeding into muscles and soft tissues
is prolonged in people with moderate and (such as the neck and throat) may be life
severe haemophilia. However, it can be threatening and need immediate treatment
normal in people with mild haemophilia. with clotting factors. Bleeding into muscle
2. Clotting factor VIII levels are low in is very painful and can be dangerous. If not
people with haemophilia A while clotting managed properly it can result in pressure
factor IX levels are low is people with on nerves, leading to nerve damage with
haemophilia B. paralysis and wasting of limbs.
3. Gene (DNA-based) tests. The genes for Cuts of the mouth and tongue, tooth
haemophilia A and B are known and can extractions and nose bleeds may ooze for
be analysed in South Africa. The test is long periods and require treatment.
expensive and not simple, and therefore 3. Internal bleeding
is only used after genetic counselling Bleeding into the organs of the abdomen
in special circumstances, including and chest is less common but may be
prenatal diagnosis, testing for carriers and spontaneous and serious. Abdominal pain
confirming a diagnosis. in a boy with haemophilia always suggests
a bleed.
4-40 What are the major Intracranial bleeding (within the skull) can
complications of haemophilia? be spontaneous or result from minor trauma,
These relate to the severity and site of bleeding. often not recognised in a child. Intracranial
A person with haemophilia may have bleeding bleeding presents as headache, vomiting, and
problems in any part of the body. Major bleeds lethargy or irritability. Urgent clotting factor
can cause death or disability and they require replacement is needed with internal bleeding.
immediate treatment with the correct clotting
factor. Minor bleeds also require treatment 4-41 When should the clinical diagnosis
and, depending on their position, may cause of haemophilia be suspected?
complications.
The diagnosis of haemophilia should be
Sites into which bleeding occurs include: suspected if a male presents with:
1. Joints 1. Large cephalhaematoma or unexplained
Joint bleeds (haemarthrosis) into the intracranial bleeding in newborns.
knees, elbows and ankles are common and 2. Excess bleeding from circumcision.
are the most disabling complication of 3. Prolonged or repeated nose bleeding, and
severe haemophilia. Joint bleeds present especially if it is from both nostrils.
with pain, swelling, stiffness and refusal 4. Prolonged oozing or renewed bleeding
to move that limb. Treatment must be after mouth injury or tooth extraction.
started with the correct clotting factor 5. Easy and excessive bruising, especially if
every 12 to 24 hours, and the joint must a firm subcutaneous lump is felt with the
be splinted. Ice packs can be used to bruise.
lessen the swelling. Failure to effectively 6. Deep muscle haematomas (collections of
treat these bleeds will eventually result in blood).
affected joints becoming fixed and not able 7. Haemarthrosis (bleeding into joints).
to move due to the damage that the blood

12. SINGLE GENE DISORDERS 77
Contact phone numbers for the Haemophilia Treatment Centres:
Town Hospital Phone number
Bloemfontein Universitas 01 405 2136
Cape Town Red Cross Children 021 658 185
Hospitals
Cape Town Tygerberg Hospital 021 938 464
Durban Haemophilia treatment 031 360 3680
centre
KwaZulu-Natal 083 265 248
East London East London Health 043 709 2370
Complex
Johannesburg Johannesburg 011 488 3294
011 488 3286
Polokwane Dr C Sutton 082 800 6778
Port Elizabeth Livingston 041 405 9111
Umtata Prof B Ogunsanwo 084 321 2482
8. Prolonged oozing or renewed bleeding the risk of developing serious complications,
after surgery or trauma. especially chronic joint disease. For major
bleeds, clotting factors should be given in
A female carrier with mild haemophilia
hospital. However, patients over two years of
may be suspected if she has a close male
age can often be treated at home.
relative (brother, son or maternal uncle) with
haemophilia and presents with heavy periods Where possible, children with severe
(menorrhagia), easy bruising or bleeding after haemophilia are now being given
trauma, surgery or childbirth. prophylactic home therapy with clotting
factor three times a week to prevent bleeding
It is suspected that the diagnosis of
episodes from occurring.
haemophilia is being missed in many cases in
South Africa. Correct diagnosis of haemophilia Once factor VIII or IX concentrate has been
is needed to be able to give the correct given, further treatment of the problems may
treatment and genetic counselling. A PTT test be needed, such as splinting during recovery,
can be used to confirm that the bleeding is due and physiotherapy to help preserve movement
to a lack of one of the clotting factors. in the recovery phase. All operations need to
take place under the cover of clotting factor
NOTE Blood for a PTT test must be drawn in a replacement to ensure that there will be no
Vacutainer tube with a blue top and must be kept excessive bleeding.
cool and reach the laboratory within a few hours.
Never give aspirin or non-steroidal anti-
4-42 What is the treatment of inflammatory drugs (e.g. Voltaren and
bleeding due to haemophilia? Indocid) to someone with haemophilia as
these drugs increase the risk of bleeding.
Bleeding is rapidly controlled by giving Haemophilia is a serious condition and must
intravenous factor VIII concentrate in be managed in partnership with a provincial
haemophilia A and factor IX concentrate in haemophilia treatment centre. Paracetamol
haemophilia B. This is to stop further bleeding (Panado) can safely be used for pain relief.
and will assist in reducing pain and lowers

13. 78 BIR TH DEFECTS
As soon as bleeding is suspected in someone with 4-44 Where can patients with haemophilia
and their parents get help?
haemophilia, immediate treatment with the
correct clotting factor concentrate must be started. The parents, family and child with
haemophilia need to be offered on-going
NOTE Vasopressin given nasally or intravenously psychosocial support as they have problems
increases the level of factor VIII and is useful in which require lifelong care. The burden of
treating mild haemophiliacs. Tranexamic acid the disorder and the care is experienced
(Cyklokapron) can be added to the clotting not only by the affected person, but also
factor infusion to help maintain clots in bleeding the family, especially parents, brothers and
from the mouth, nose or tooth sockets. sisters. Support, help and reassurance in these
circumstances may be obtained from:
4-43 What genetic counselling
1. Doctors, nursing staff (especially
is needed by people with
haemophilia and nursing staff trained
haemophilia and their families?
in genetics), genetic counsellors,
Genetic counselling is an important part of physiotherapists and social workers.
the care of people with haemophilia, and 2. A Patient/Parent support group. These
their families. All need to be educated and groups play a vital role in offering
informed on: information and support to people
1. The diagnosis: The clinical features and affected with congenital disability. There
the blood tests to confirm the diagnosis. is currently a very strong haemophilia
2. The pattern of inheritance: About 80% support group in South Africa.
of males with haemophilia have a mother South African Haemophilia Foundation
who is a carrier of the single gene defect (011 849 1733) and the Haemophilia
on one of her X chromosomes. About Treatment Centre (031 360 3680).
10% of these carrier mothers have mild
symptoms and signs of haemophilia. The 4-45 What is the risk for parents,
20% of males with haemophilia, who do with a son with haemophilia, having
not have carrier mothers (no family history affected sons in future pregnancies?
of bleeding), have a new mutation of their
haemophilia gene. If the mother is a carrier of the abnormal gene
3. What care is needed: What haemophilia then in each of her future male pregnancies
means for the affected person and what can she will have a 1 in 2 (50%) chance of having a
be done to treat the various problems. son affected with haemophilia.
4. Risks for future children also having If the mother is NOT a carrier of an abnormal
haemophilia: Parents of a child with haemophilia gene then her risk for having
haemophilia need to understand the risk another son with haemophilia is very small.
of having another child with haemophilia.
They must also be told about their options NOTE With no family history of haemophilia, it
and possibilities for reducing this risk and has recently been shown that the mother may
preventing the birth of another affected be a carrier, having inherited a new mutation
child. The parents also need to know from her elderly father. He would not have
of the risk that their daughters have for haemophilia but his sperm had a new mutation
in a haemophilia gene on the X chromosome.
inheriting the abnormal gene from their
mother, and therefore being a carrier.
They need to understand what this will
mean for the daughters.

14. SINGLE GENE DISORDERS 79
4-46 What is the risk for parents, He will give his X chromosome, with the
with a son with haemophilia, having abnormal haemophilia gene, to his daughters
haemophilia carrier daughters? who will all, therefore, be carriers of the
abnormal haemophilia gene.
The risk is 1 in 2 (50%). This is the same as
the risk of having an affected son. The carrier
mother will give her X chromosome with the 4-49 Can haemophilia be prevented?
abnormal gene to half of her children. The Yes. Because the abnormal gene for
carrier daughters, like their mothers, have haemophilia can be tested for, a woman who is
the same risks (50%) of passing the abnormal a carrier of this abnormal gene can be offered
haemophilia gene on to their sons and prenatal diagnosis. This is done after she and
daughters. her partner have had genetic counselling.
It is best to provide genetic counselling and
4-47 How can you find out
to determine whether the woman is a carrier
whether the mother of a child
before she falls pregnant. Prenatal diagnosis is
with haemophilia is a carrier?
then done early in pregnancy. This is carried
If a couple has a son with haemophilia, then out by obtaining fetal cells by amniocentesis,
it is important to find out if his mother is a and testing these cells to see if they have an
carrier of an abnormal haemophilia gene. abnormal haemophilia gene (A or B).
There are two ways of finding this out:
NOTE The cells of the placenta can be
1. If the mother of the affected son has one obtained by chorionic villous biopsy,
other affected male member in her close even earlier in pregnancy. The fetus and
family, such as a brother or uncle, then placenta have the same genes.
she is almost certainly a carrier of the
abnormal gene for haemophilia. 4-50 What special circumstances must
2. If the mother does not have such an be considered in haemophilia?
affected close relative then she or her
son with haemophilia may have a new 1. If a woman is suspected of being a carrier
mutation for the abnormal gene. The best of a haemophilia gene, the diagnosis
way then to find out if the mother is a must be confirmed or excluded before
carrier of the abnormal gene is for her and she becomes pregnant or as early in the
her son to have a gene (DNA) test. pregnancy as possible. This allows for
genetic counselling and the option of
prenatal diagnosis to be offered. Ten
4-48 Can a father with haemophilia
percent of carriers may bleed heavily
have affected children?
during a normal delivery or caesarean
Men have one X and one Y chromosome. section. There is also a small risk (1–2%)
If a man has haemophilia he will have of a male fetus, affected with severe
an abnormal haemophilia gene on his X haemophilia, having an intracranial bleed
chromosome but not on his Y chromosome with a vaginal delivery. Women who are
(i.e. an X-linked recessive disorder). When he known carriers, or at risk of being carriers,
has children he gives his Y chromosome, with of an abnormal haemophilia gene should
the no haemophilia gene, to his sons who will be referred to a haemophilia treatment
get their X chromosome from their mother. centre before and during pregnancy.
Therefore, if the mother is not a carrier of an 2. In infants suspected of having
abnormal haemophilia gene, their sons will haemophilia, circumcision should not
not have haemophilia. be done and they should not be given
intramuscular injections. Immunisations

15. 80 BIR TH DEFECTS
can be given subcutaneously. They must be which affect their schooling and socialisation.
referred for diagnostic tests. They are not intellectually disabled.
3. People with haemophilia should avoid
medications that may cause bleeding. The 5. How common is Waardenburg
most common and important of these is syndrome in South Africa?
aspirin and the other non-steroidal (anti-
inflammatory) analgesics (pain killers). It is not common (about one in 30 000
Paracetamol (Panado) can be safely used people). However, about 4% of people with
for pain relief. severe deafness have the condition.
CASE STUDY 1 CASE STUDY 2
A woman with Waardenburg syndrome The first-born infant of black parents has
delivers her first-born infant who also has a very pale skin and hair with light-brown eyes.
white forelock. She asks whether all her infants They notice that the child has abnormal eye
will have the same problem. movements and appears to have poor vision.
The nurse at the local clinic tells them that
1. What are the main features of they should use skin cream on the infant to
Waardenburg syndrome? prevent sunburn. The clinic does not have
sun protection cream and the parents cannot
Very blue eyes, bushy eyebrows, deafness (25
afford to buy the cream.
to 50%) and a white forelock (30 to 40%).
Premature greying of the hair and partial
albinism is common. 1. What is the likely diagnosis in this infant?
The infant probably has oculocutaneous
2. How is Waardenburg inherited? albinism (OCA) as there is lack of pigment in
the skin, hair and eyes. This is the common
It is usually inherited as an autosomal
form of albinism in southern Africa.
dominant disorder. This woman’s child has
inherited her dominant gene for Waardenburg
syndrome. Each of her future children will 2. Are eye problems common
have a 50% chance of inheriting the condition. in this condition?
Yes. All people with OCA have eye problems
3. Is there always a family history of the and most have poor vision. This infant has
condition if a child presents with the the typical jerky eye movements known as
features of Waardenburg syndrome? nystagmus.
No. As with many autosomal dominant
disorders, the condition may appear as a 3. Why is it important to use sun
new mutation and will not be inherited protection cream in these children?
from a parent. About a third of patients with Because they lack adequate pigment (melanin)
Waardenburg syndrome do not have a family to protect the skin from the ultraviolet rays
history of the condition. of the sun, they suffer severe skin damage.
Sunburn and blistering are common, resulting
4. What is the main complication in rapid aging of the skin.
of Waardenburg syndrome?
Severe sensory deafness affecting both ears.
As a result they often have speech difficulties

16. SINGLE GENE DISORDERS 81
4. What skin complications should 3. Are people with oculocutaneous
be looked for and treated? albinism intellectually disabled?
Infections and cancer. No. They have normal intelligence. However,
their many eye problems results in poor vision
5. What is the life expectancy in people and this may interfere with their schooling.
with oculocutaneous albinism?
4. Why may neighbouring children
Many die young as a result of skin cancer. This
be afraid of someone with
emphasises the importance of sun protection.
oculocutaneous albinism?
The life expectancy of people with OCA in
South Africa is not known. Because people with oculocutaneous albinism
look different. Children should not be afraid
of people with oculocutaneous albinism
CASE STUDY 3 as they are normal people except for their
colouring. There are also many myths about
A woman, whose husband has oculocutaneous people with oculocutaneous albinism. In some
albinism, visits her general practitioner as they communities these people are believed to have
plan to start their family. She wants to know special powers.
the risk of their children also being affected.
She mentions that he gets upset as many 5. Can oculocutaneous
people think he is intellectually disabled and albinism be prevented?
some children are afraid of him The gene for OCA is known and, therefore,
prenatal diagnosis is possible. Couples at risk
1. What is the pattern of inheritance of having a child with OCA should receive
in oculocutaneous albinism? genetic counselling, preferably before they
It is inherited as an autosomal recessive start a family.
disorder. Therefore, the father must have
two abnormal genes for melanin production
(homozygous). Each of his children will have CASE STUDY 4
a 50% chance of inheriting one of his genes
containing the single gene defect for OCA. If A newborn infant bleeds very heavily after
the mother does not have this gene, then these circumcision. The mother reports that her
children will appear normal but will be carriers uncle died of haemorrhage as a teenager after
(heteroygotes). It is possible to test the mother an operation, and that her brother is severely
to see whether she is a carrier. If she is, then the disabled due to repeated bleeds into his joints.
couple should be sent for genetic counselling. She and her husband are well and have never
had a bleeding problem.
2. How common is oculocutaneous
albinism in South Africa? 1. How does haemophilia present clinically?
The prevalence in the black population is 1 in With excessive bleeding. Heavy bleeding
3900, making it the commonest single gene after a circumcision is a typical way that
disorder in the country. The prevalence in haemophilia may present. Patients may bleed
other ethnic groups is unknown. spontaneously or after trauma or surgery.

17. 82 BIR TH DEFECTS
2. Is repeated bleeding into joints a clinically well without a bleeding problem
common way that haemophilia presents? although 10% of carrier mothers may have a
mild problem.
Yes. Patients with severe haemophilia, who
have less than 1% of the normal clotting factor
activity, often bleed into big joints such as the 5. How is the diagnosis of
knee, elbow or ankle. Repeated bleeds damage haemophilia usually confirmed?
the joint resulting in pain and stiffness. The PTT (partial thromboplastin test) is
abnormal and the concentration of either
3. Why do people with haemophilia factor VIII (haemophilia A) or factor
bleed excessively? IX (haemophilia B) is low. The lower
the concentration the more severe is the
An inadequate amount of clotting factor
haemophilia. Haemophilia A is more common
VIII (in haemophilia A) or factor IX (in
than haemophilia B.
haemophilia B).
6. How should a patient with a big
4. How is haemophilia inherited?
bleed due to haemophilia be treated?
Both haemophilia A and B are inherited as X-
The missing clotting factor should urgently
linked recessive disorders. The females in the
be replaced by intravenous transfusion of
family carry the recessive gene on one of their
factor VIII for haemophila A or factor IX
X chromosome. Fifty percent of their male
for haemophilia B. This is best done by
children will inherited the X chromosome
immediate consultation with a haemophilia
with the abnormal gene, and as a result will
treatment centre.
have haemophilia. Both parents are usually