4 Single gene disorders

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Introduction to single gene disorders

4-1 What is a single gene defect?

This is an abnormality (mutation) in a single gene which results in a genetic disorder (congenital disorder). Single gene defects cause many structural and functional (biochemical or metabolic) congenital disorders. The number of chromosomes is normal with a single gene defect.

A single gene defect may be inherited in a number of different patterns:

  1. Autosomal dominant, e.g. Waardenburg syndrome.
  2. Autosomal recessive, e.g. oculocutaneous albinism.
  3. X-linked recessive, e.g. haemophilia.

In addition, a single gene defect may be due to a new mutation (autosomal dominant or X-linked recessive). With a new mutation affected individuals will not have a family history of that condition.

Single gene defects cause clinical conditions resulting from mutations in a single gene.

Waardenburg syndrome, oculocutaneous albinism and haemophilia are typical examples of disorders due to single gene defects with different patterns of inheritance. They illustrate many of the problems and principles of care and management for people with single gene defects, and their families.

4-2 What are the common single gene disorders?

The most common autosomal dominant disorders are:

  1. Polydactyly (extra digits)
  2. Achondroplasia (short-limbed dwarfism)
  3. Neurofibromatosis
  4. Waardenburg syndrome

The most common autosomal recessive disorders are:

  1. Sickle cell anaemia.
  2. Thalassaemia.
  3. Oculocutaneous albinism.
  4. Cystic fibrosis (an autosomal recessive disorder common in people of European descent).

The most common X-linked recessive conditions are:

  1. Red–green colour blindness.
  2. Haemophilia.
  3. Glucose-6-phosphate dehydrogenase deficiency (G6PD).

Some single gene disorders are more common in specific populations or regions, e.g. sickle cell anaemia in West Africa, cystic fibrosis in Europe, thalassaemia in Mediterranean countries, polydactyly in black South Africans. Most autosomal recessive conditions are found in, or come from, tropical countries. Cystic fibrosis is the common autosomal recessive disorder in people of European descent.

Some conditions, such as polycystic kidneys, osteogenesis imperfecta, retinitis pigmentosa and mental retardation, may be inherited by more than one mode of inheritance, e.g. in some families as a dominant disorder while in other families as a recessive disorder.

Table 4-1: Examples of single gene disorders and their mode of inheritance

Autosomal dominant Autosomal recessive X-linked recessive
Achondroplasia Adrenogenital syndrome Duchenne muscular dystrophy
Apert syndrome Congenital hypothyroidism Fragile X syndrome
Crouzon syndrome Cystic fibrosis Glucose 6 phosphate dehydrogenase deficiency
Hypercholesterolaemia Fanconi anaemia Haemophilia
Huntington disease Galactosaemia Hunter syndrome
Marfan syndrome Oculocutaneous albinism Incontinentia pigmenti
Neurofibromatosis Phenylketonuria Vitamin D resistant rickets
Polydactyly Sickle cell anaemia
Treacher Collins syndrome Spinal muscular atrophy
Tuberous sclerosis Tay Sachs disease
Waardenburg syndrome Thalassaemia

Waardenburg syndrome

4-3 What is Waardenburg syndrome?

Waardenburg syndrome is an inherited disorder that is made up of a recognisable collection of clinical features including deafness. It is the commonest cause of inherited deafness associated with a known syndrome in southern Africa.

4-4 How is Waardenburg syndrome inherited?

Waardenburg syndrome is an autosomal dominant disorder:

  1. About two thirds of individuals with Waardenburg syndrome have inherited the affected dominant gene, and therefore the clinical condition, from an affected parent.
  2. The remaining third of people with Waardenburg syndrome have the condition as the result of a new gene mutation. Therefore their parents are clinically normal and neither has the affected gene.
The new gene mutation for Waardenburg syndrome is associated with advanced paternal age (having a father older than 50 years) at the time of birth.

Waardenburg syndrome is inherited as an autosomal dominant disorder.

4-5 How common is Waardenburg syndrome?

Waardenburg syndrome is rare. It occurs in about 1 in 30 000 people in all populations.

In southern Africa approximately 4% of people with profound deafness have Waardenburg syndrome. This is similar to studies from other parts of the world where the prevalence of Waardenburg syndrome amongst deaf people varies from 2% to 5%.

4-6 What are the main clinical features of people with Waardenburg syndrome?

The main clinical features of Waardenburg syndrome are:

  1. Very blue eyes (sapphire blue). The iris of both eyes can have an extraordinary blue colouring which is very noticeable in black Africans who usually have brown eyes. In some cases, only one eye or part of the iris has distinctive colouring and the other eye or part of the iris has the normal eye colour (heterochromia).
  2. Some people with Waardenburg syndrome have abnormal tear ducts. This can cause repeated eye infections.
  3. Eyebrows. The inner (medial) part of the eyebrow is very bushy and often the eyebrows meet in the middle (synophrys).
  4. Deafness. Sensory (nerve) deafness is the most serious feature of Waardenburg syndrome. It usually involves both ears and is severe. Deafness is found in 25% to 50% of people with Waardenburg syndrome.
  5. A white forelock. Between 30% and 40% of people with Waardenburg syndrome have a white or grey patch of hair in the middle 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.
  6. Early greying of hair and eyebrows. This 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 little or no pigmentation.

Individuals with Waardenburg syndrome can be deaf and have a characteristic white forelock.

There are considered to be two main forms of Waardenburg syndrome, types I and II, both of which have similar features but which can be told apart because type I has dystopia canthorum and type II does not. Dystopia canthorum is the name given to the facial feature in which the inner corners (canthi) of each eye are further apart than normal and the nasal bridge is broad. Careful examination of the lower eyelid will also show that the openings to the tear ducts (lacrimal puncta) are further away from the inner corners of the eye than usual. People with Waardenburg syndrome type II do not have these features. Deafness is 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 (over 50%) form of Waardenburg syndrome.

4-7 Must a person have all these features to be diagnosed with Waardenburg syndrome?

No. Three or more of the main features must be present to consider the clinical diagnosis. In Waardenburg syndrome, as is found in many other syndromes, the number and severity of the clinical features present can vary greatly. This is called variation in expression of the syndrome (i.e. not all the features are expressed).

4-8 Is there a test to confirm the diagnosis of Waardenburg syndrome?

Yes. The gene for Waardenburg syndrome can be identified to confirm the diagnosis. However, the test is expensive and currently not undertaken in South Africa.

4-9 What are the major complications of Waardenburg syndrome?

  1. Deafness and the problems associated with this, including lack of speech and communication ability, schooling problems and social stigmatisation.
  2. Recurrent eye infections (conjunctivitis) in infants and children caused by the problems with the tear ducts.

4-10 Are people with Waardenburg syndrome intellectually disabled?

No. However, infants and children with deafness from any cause, including Waardenburg syndrome, are often considered to be developmentally delayed. This is because of the lack of speech and inability to communicate. If the problem is discovered early and appropriate speech therapy started, many of the developmental problems may be overcome and the person is shown to be of normal intelligence.

4-11 What care is available for people with Waardenburg syndrome?

  1. Early diagnosis:

    In people with Waardenburg syndrome, as with all cases of infant and childhood deafness, it is very important to diagnose their deafness as early as possible to ensure they can start intervention programmes as early as possible. This will ensure the best long-term outcome for the person’s communication ability. The early clinical confirmation of the diagnosis of Waardenburg syndrome is also important so that genetic counselling can be offered to the family.

  2. Managing the deafness:

    The early diagnosis of deafness, in infancy if possible, is important so speech and communication therapy can be started early ensuring the best long-term results. Assessment to decide if hearing aids may benefit the infant or child should also be done as early as possible. Assessment and initial speech therapy need to be done at a specialised centre. Ongoing day-to-day speech therapy in areas far from such centres may be made possible for infants and young children with the help of community-based rehabilitation workers. However, to achieve the best results, these children will need to regularly attend centres for specialised ongoing assessment and therapy and eventually need to go to schools for the auditory disabled (deaf).

  3. Manage repeated eye infections:

    Conjunctivitis needs to be treated with repeated swabbing of the eye with clean water (boiled and then cooled), massaging the tear duct, and antibiotic drops or ointment if indicated. If the problem recurs often then surgical probing of the tear duct can be performed.

  4. Genetic counselling and psychosocial support.

4-12 What genetic counselling is needed by parents who have a child with Waardenburg syndrome?

Genetic counselling is a major part of the care of people with Waardenburg syndrome and their family, especially the parents. The parents need to be educated and informed about:

  1. The diagnosis.
  2. The cause of Waardenburg syndrome. That Waardenburg syndrome is a genetic disorder, inherited in an autosomal dominant manner. However, in one third of patients it may occur for the first time in a family as a new mutation.
  3. What Waardenburg syndrome means for the affected person and what can be done to treat the various problems.
  4. The risks for parents with a child with Waardenburg syndrome having a child with Waardenburg syndrome in future pregnancies and their options for reducing this risk and preventing the birth of another affected child.

The parents, family and child with Waardenburg syndrome need to be offered ongoing psychosocial support as with all individuals who have a congenital disability. There is currently no support group for Waardenburg syndrome in South Africa.

4-13 What is the risk for parents of a child with Waardenburg syndrome having affected children in future pregnancies?

To assess this risk, the parents have to be examined to see if one of them has signs of Waardenburg syndrome. Because of variation of expression of the syndrome it may not have been diagnosed in one of them, as their symptoms and signs may not be as severe or numerous as in their child. For example, an affected parent may not necessarily be deaf.

If a parent is diagnosed with Waardenburg syndrome, then all future children of that parent have a 1 in 2 (50%) risk of having Waardenburg syndrome. These children with Waardenburg syndrome, when they have grown up and have their own children, will also have a 1 in 2 (50%) risk of passing the syndrome to each of their offspring. This is typical of an autosomal recessive disorder.

If both parents of a child with Waardenburg syndrome are clinically normal, then the cause of Waardenburg syndrome in the child is due to a new mutation. Future children of that couple will have only a very small risk of being affected with Waardenburg syndrome. But the affected child will have a 1 in 2 (50%) risk of having an affected child.

4-14 Can Waardenburg syndrome be prevented?

Yes. Because the genes for Waardenburg syndrome are known, it is possible to do prenatal diagnosis. However, as the test is not currently offered in South Africa, prenatal diagnosis of Waardenburg syndrome is not practical.

Oculocutaneous albinism

4-15 What is albinism?

Albinism is an inherited condition. The clinical signs and symptoms of albinism are caused by a lack of melanin in the cells of the body. Melanin is the pigment that gives colour to the skin, hair and eyes.

Albinism occurs in many animals such as the white lions of Timbavati.

4-16 Are there different types of albinism?

Yes, there are different forms of albinism:

  1. Albinism with a lack of pigment in the eye (oculo-) plus skin (cutaneous) and hair. This is called oculocutaneous albinism or OCA.
  2. Albinism which only affects the eyes and not the skin or hair. This is called ocular albinism.

Oculocutaneous albinism is the result of a lack of pigment in the eyes, skin and hair.

Oculocutaneous albinism is further classified into types I and II. In sub-Saharan Africa, including South Africa, oculocutaneous albinism type II is the most common form of albinism found.

4-17 How is oculocutaneous albinism inherited?

OCA is inherited as an autosomal recessive condition. Therefore, a person affected with OCA has received 2 copies of the abnormal gene (homozygous) that is responsible for melanin production (i.e. one abnormal gene from each parent). As a result, the cells of an affected individual are unable to produce normal amounts of pigment and, therefore, they are very pale.

Each parent of an affected individual has 1 normal and 1 abnormal copy of the pigment gene (i.e. is heterozygous). Because they have 1 normal gene that can produce melanin, they have normal pigmentation and do not show signs of OCA.

Oculocutaneous albinism is inherited as an autosomal recessive disorder.

4-18 How common is oculocutaneous albinism?

Oculocutaneous albinism (OCA) is the commonest single gene disorder in South Africa. The population prevalence of OCA in the black South African population is 1 in 4000. However, it is even higher in communities that practise intermarriage (consanguinity). The population prevalence of OCA in other ethnic groups in South Africa is unknown.

The population prevalence of OCA is similar throughout most of sub-Saharan Africa, varying 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 valley. In comparison, in Europe, the prevalence of OCA varies between 1 in 10 000 and 20 000.

Oculocutaneous albinism is the commonest single gene disorder in South Africa.

4-19 What are the main clinical features of oculocutaneous albinism?

People affected with OCA have normal physical and facial features, but have markedly decreased pigmentation of their skin, hair and eyes resulting in all these features being pale. In people with darker skin tones OCA is easily recognised. In people with lighter skin tones, OCA is less obvious. The features of OCA are:

  1. Skin

    They have pale skin which is very sensitive to sunlight.

    They may have small spidery pigmented patches called ephelides scattered over their bodies, mainly on sun-exposed areas such as the arms and faces.
  2. Hair

    A black African with OCA usually has pale or corn-coloured hair. The hair colour in a few individuals may be brown or reddish (rufous).

  3. Eyes

    Black African people with OCA have brown eyes, but their eyes may be lighter brown than normal. They have numerous eye problems.

4-20 What eye problems are common in people with oculocutaneous albinism?

  1. Photophobia: Sensitivity to bright light and glare.
  2. They all have nystagmus. This is jerky movements of the eyes in a horizontal or vertical direction or both.
  3. Most have poor vision (96%). About two thirds are short sighted (myopia) and one third long sighted (hyperopia).

All people with oculocutaneous albinism have problems with their eyesight.

Most people with OCA have astigmatism (92%) and poor depth judgment. They also have abnormal visual pathways since the gene for melanin production is responsible for the development of the optic nerve tracks from the eye to the visual centre at the back of the brain. Because of their abnormal visual pathways they do not have binocular vision like people without OCA.

4-21 What are the major complications of oculocutaneous albinism?

  1. Skin

    Normally, melanin prevents the sun’s ultraviolet rays being absorbed by the skin. If melanin is not present in adequate amounts, the ultraviolet rays in sunlight penetrate and damage the skin. Problems resulting from a lack of pigmentation in the skin include:

    • Easy sun-burning and blistering.
    • Rapid ageing of the skin which leaves it thin, dry and it is easily damaged. These areas of skin often become infected.
    • Skin cancer (squamous cell carcinoma). People with OCA are at high risk of developing cancer of the skin on sun-exposed areas, especially if the person does not take precautions to protect themselves from the sun. People living nearer the equator, where the sunlight is stronger, are at a higher risk.
    • Early death from skin cancer is a serious risk for people with OCA.
  2. Eyes
    • Lack of pigment in the eyes can result in sunlight-induced damage to the eyes. This will cause further weakening of visual ability.
    • As individuals with OCA have abnormal eyesight, they may experience learning difficulties and job discrimination in later life.
  3. Social stigmatisation
    • Throughout Africa, myths or legends regarding the birth, life and death of people with OCA are common. These myths can affect people’s attitudes to people with OCA, mostly negatively but in some populations positively. In many regions of sub-Saharan Africa there is isolation and stigmatisation of people with OCA.

Research from South Africa indicates that people with OCA are now generally well accepted in the community, and they in turn appear to be reasonably well adjusted. Myths regarding people with OCA are, however, plentiful, and it has been reported that mothers of newborns with OCA experience problems bonding with their infants and may suffer from depression, similar to that described by mothers with other congenital disorders.

Skin cancer is a common complication of oculocutaneous albinism.

4-22 What are some of the South African myths regarding people with oculocutaneous albinism?

  1. Birth myths:

    These are used to try and explain the unexpected birth of an infant with OCA. They include that the birth is a punishment for some supposed bad deed committed by the parent(s); that the mother conceived during menstruation; that the mother must have come into contact with a person with albinism during pregnancy; that the mother ate an excess of certain foods or had an infection during pregnancy.

  2. Life myths:

    These are about special qualities that people with OCA supposedly have. One of the common beliefs is that people with OCA may have special religious, spiritual or supernatural power. People with OCA are often considered either very intelligent or intellectually disabled.

  3. Death myths:

    The death of people with OCA is surrounded with superstition. It is widely believed that they do not die, but rather disappear or vanish.

4-23 Are children with oculocutaneous albinism intellectually disabled?

No. Children with OCA generally have a normal intelligence and are not intellectually disabled. Due to their visual disability, infants and young children may present with evidence of developmental delay. Older children may have schooling problems due to their poor vision or psychosocial problems. However, if these problems are recognised early and correctly treated with eye and visual care, early intervention programmes and counselling, they can be overcome.

4-24 What is the life expectancy of children with oculocutaneous albinism?

The life expectancy of people with OCA should be similar to that of people without OCA. However, due to the high risk of developing skin cancer, many unfortunately die in early adult life if not correctly treated and counselled. In Tanzania and Nigeria, countries in the tropics and close to the equator, only 10% of people with OCA live longer than 30 years. No figures on life expectancy are currently available for South Africa. However, it is considered to be higher than the figure for Tanzania and Nigeria as the majority of South Africa is outside of the tropics. Stigmatisation has also led to a high rate of early, unnatural deaths of those affected by OCA, with body parts being used in certain ceremonies.

Many people with oculocutaneous albinism die of skin cancer.

4-25 What is the correct care for people with oculocutaneous albinism?

  1. Early clinical diagnosis:

    The first step in caring for people with OCA is to make an early, correct diagnosis. OCA is a clinical diagnosis and is usually made at the birth of the infant, especially in the black African infants in whom the diagnosis is very obvious. However, the clinical signs can be more difficult to recognise in white or Asian infants.

  2. Good skin and eye care:

    Good skin and eye care is essential to prevent skin cancer and progressive loss of eyesight.

  3. Neurodevelopmental therapy, special education and rehabilitation.

    This should be provided in the community, if possible, to enable children affected to learn and develop normally.

  4. Genetic counselling and psychosocial support.

4-26 What skin care is needed for children with oculocutaneous albinism?

It is essential for people with OCA to reduce their exposure to sunlight to the greatest extent possible. As it is not possible for a person with OCA to remain out of the sun continually, when they do go outdoors they should wear clothes to cover as much skin as possible, i.e. long trousers or skirts, long-sleeved tops or shirts, and hats with wide brims.

Sun-exposed skin, especially hands, arms and face, should be covered with cream containing sunscreen (sun barrier creams). Cream with sun protection factor (SPF) of 30 or greater must be used. Moisturising cream should be used on dry, cracking or chaffed skin, and skin infection should be treated vigorously with antiseptics and antibiotics if clinically indicated. Unfortunately, many clinics do not have sun barrier creams because they are expensive.

Adolescents and adults with OCA should be aware of the dangers of skin cancer. They should be taught how to recognise areas of skin cancer so that they know what to look for to be able to suspect and possibly diagnose cancer as early as possible (e.g. sores that do not heal). In addition, they should have yearly examinations to exclude the development of skin cancer.

Good skin protection against sunlight is essential to prevent skin cancer.

4-27 What eye care is needed for children with oculocutaneous albinism?

People with OCA need to protect their eyes from the harmful effects of sun and bright light by avoiding it where possible and wearing protective eyewear (appropriate dark glasses with an ultraviolet screen) and broad-brimmed hats. In this way, further damage to their visual disability can be minimised.

All people with OCA should have regular ophthalmic or optometric assessments from infancy. This is necessary to ensure they obtain the correct glasses and treatment for their individual problems. This gives them the best chance of reasonable vision and ensures that their sight is not damaged by the lack of eye care.

Good eye care, protection from the sun, and the correct glasses are essential to protect eye sight.

4-28 What neurodevelopmental therapy, community-based rehabilitation and special education are needed for children with oculocutaneous albinism?

  1. In infants and children with severe visual disability it may be necessary for them to receive neurodevelopmental therapy, e.g. occupational therapy at their local hospital.
  2. If specialised therapy is not available in their area they will have to rely on local community-based rehabilitation services.
  3. When children with OCA reach school-going age, decisions will need to be made regarding school placement. Where possible, children with OCA should be encouraged to attend mainstream schools. Efforts to assist them in a such schools may be necessary, e.g. placement in the front row of the class. If, however, their visual disability is too severe, then scholars may need to be placed in a school for the visually disabled.

4-29 What genetic counselling is needed for families with oculocutaneous albinism?

Genetic counselling is a major part of the care of people with OCA and their family, especially their parents. The parents need to be educated and informed about:

  1. The diagnosis, which is a clinical one and is usually obvious.
  2. The cause of OCA. Explain that OCA is a genetic disorder, inherited in an autosomal recessive manner. This information can be used to try and dismiss the myths about why an infant with OCA is born to a couple.
  3. What OCA means for the affected person and what can be done to prevent and manage the various problems. It is essential to stress that every effort must be made to avoid 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 eyewear and using sunscreen cream.
  4. The risks for parents with an OCA affected infant having another child with OCA in future pregnancies. Their options for reducing the risk of having another infant with OCA should be discussed.

The parents, family and person with OCA need to be offered ongoing psychosocial support.

4-30 What is the risk for normal parents of a child with oculocutaneous albinism having other affected children in future pregnancies?

OCA is an autosomal recessive condition. As carriers of a single abnormal OCA gene, parents of a child with OCA have a 1 in 4 risk (25%) of having a further affected child in every future pregnancy. With another partner, the chance of either parent having an affected child is very small.

4-31 How can oculocutaneous albinism be prevented?

The gene for OCA has been identified and, therefore, it is possible to offer prenatal 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 before conception, or in the first 10 weeks of the pregnancy. The prenatal gene test is done on fetal cells obtained by amniocentesis at 16 weeks. Once the result of the prenatal test is available, further genetic counselling will be necessary to discuss these results.

4-32 Why do people with oculocutaneous albinism, and their family, need psychosocial support?

People with OCA, as with all individuals who have a congenital disability, suffer lifelong problems which require lifelong care. The burden of the disorder is experienced not only by the affected person, but also the family, especially parents and siblings. Mothers of newborns with OCA need psychosocial support to help them accept and bond with their infant, and overcome possible depression. In addition, the problem is genetic and thus there is the possibility for the parents, the affected person and other family members to also have other children affected with OCA. Support, help and reassurance in these circumstances may be a lifelong need.

4-33 Who can offer psychosocial support?

Professional psychosocial support can be obtained from:

  1. Doctors, nurses (especially nurses with postgraduate genetic training), genetic counsellors and neurodevelopmental therapists.
  2. Social workers.
  3. Patient/parent support groups. These groups play a vital role in offering information and support to people affected with congenital disability.
There is a strong support group for people with OCA in South Africa through the Albinism Association of South Africa (ASSA), P O Box 9881, Johannesburg, 2000. Tel: 011 838 6529. Website: www.albinism.org.za


4-34 What is haemophilia?

Haemophilia is an inherited, lifelong bleeding disorder which affects mainly males.

There are two types of haemophilia: haemophilia A and haemophilia B. Haemophilia A (classical haemophilia) is the common form of haemophilia. Both types present clinically as a bleeding problem.

4-35 Why do patients with haemophilia bleed excessively?

Haemophilia A is caused by a lack of normal functioning clotting factor VIII (eight) while haemophilia B is caused by a lack of normally functioning clotting factor IX (nine).

It is the low level of function, rather than a low concentration of the clotting factor in the blood, which results in an increased tendency to bleed. The single gene defect results in the formation of a defective clotting factor, which does not function normally.

Haemophilia is a bleeding disorder due to the lack of a normal clotting factor.

4-36 How is haemophilia inherited?

Both types of haemophilia are inherited as X-linked recessive disorders. There are different single gene defects on the X chromosome for haemophilia A and haemophilia B on the X chromosome.

A woman with a haemophilia gene (i.e. an abnormal gene) on only one X chromosome is a carrier (i.e. she is a heterozygote). Because she has a normal gene on her other X chromosome, she will still be able to produce enough clotting factor. If she passes the X chromosome containing the abnormal gene on to her daughter, then her daughter will also be a carrier.

If a son inherits the X chromosome with the haemophilia gene from his mother, he will have haemophilia as his short Y chromosome does not have the gene to produce the clotting factor.

About 30% of people with haemophilia have no family history of bleeding as the disorder is due to a new mutation.

Haemophilia is inherited as an X-linked recessive condition. Women carry the abnormal gene and their sons are at 50% risk of inheriting haemophilia.

4-37 Can females have haemophilia?

Yes. About 10% of female carriers have signs of mild haemophilia. All patients with moderate or severe haemophilia are males.

If a daughter inherits a haemophilia gene from her carrier mother and another from her haemophiliac father, both her X chromosomes will contain the abnormal gene and she will have haemophilia. This is very rare.

4-38 How common is haemophilia?

  1. Haemophilia A occurs in approximately 1 in 5000 males throughout the world.
  2. Haemophilia B occurs in approximately 1 in 40 000 males throughout the world.

In South Africa, haemophilia A has been found in 1 in 5000 white males but only 1 in 20 000 black males. Due to poor socioeconomic conditions and inadequate access to health care in many black communities, some black people with haemophilia A may not be diagnosed and registered. Others may die very young with severe bleeding without the diagnosis being made. Therefore the population prevalence is less than expected.

4-39 What are the main clinical features of people with haemophilia?

People with haemophilia present with excessive bleeding. The bleeding may be in the skin and mucous membranes (bruising), muscle, joints, internal organs or brain. Infants usually bleed into soft tissues while older boys usually bleed into joints.

The severity and frequency of bleeds depends on the concentration of clotting factors VIII and IX in the patient’s blood:

  1. People with mild haemophilia only have 5% to 35% of the normal factor VIII or IX level. They usually only bleed following severe trauma and at surgery. Because bleeding is not a major problem they may only be diagnosed later in life.
  2. People with moderate haemophilia have between 1% and 5% of the normal factor VIII or IX level and they bruise easily. They usually bleed excessively following trauma, surgery or dental care but rarely have spontaneous bleeds. They usually do not have serious problems with bleeding into joints. Diagnosis before the age of 5 years is possible.
  3. People with severe haemophilia have less than 1% of the normal factor VIII or IX level and may bleed spontaneously or with minimal trauma. They can bleed in any part of the body but some parts such as the large joints (knees, ankle and elbow) are more at risk of injury and bleeding. Diagnosis should occur in the first year of life.

Bleeding is unusual in newborns but infants with haemophilia can bleed from circumcision sites. Infants with severe haemophilia will bleed into muscles from injection or needle-stick sites or spontaneously into cephalhaematomas or within the skull (intracranial bleed).

4-40 Are there tests to confirm the diagnosis of haemophilia?

Yes. If haemophilia is suspected, the following tests can be done to confirm the diagnosis:

  1. Partial thromboplastin time (PTT). This is prolonged in people with moderate and severe haemophilia. However, it can be normal in people with mild haemophilia.
  2. Clotting factor VIII levels are low in people with haemophilia A while clotting factor IX levels are low in people with haemophilia B.
  3. Gene (DNA-based) tests. The genes for haemophilia A and B are known and can be analysed in South Africa. The test is expensive and not simple, and therefore is only used after genetic counselling in special circumstances, including prenatal diagnosis, testing for carriers and confirming a diagnosis.

4-41 What are the major complications of haemophilia?

These relate to the severity and site of bleeding. A person with haemophilia may have bleeding problems in any part of the body. Major bleeds can cause death or disability and they require immediate treatment with the correct clotting factor. Minor bleeds also require treatment and, depending on their position, may cause complications.

Sites into which bleeding occurs include:

  1. Joints

    Joint bleeds (haemarthrosis) into the knees, elbows and ankles are common and are the most disabling complication of severe haemophilia. Joint bleeds present with pain, swelling, stiffness and refusal to move that limb. Treatment must be started with the correct clotting factor every 12 to 24 hours, and the joint must be splinted. Ice packs can be used to lessen the swelling. Failure to effectively treat these bleeds will eventually result in affected joints becoming fixed and not able to move due to the damage that the blood causes in the joint. Arthritis can develop. Physical disability resulting from joint damage is a major problem for people with haemophilia in developing countries.

  2. Muscle and soft tissues
    • Bleeding into muscles and soft tissues (such as the neck and throat) may be life threatening and need immediate treatment with clotting factors. Bleeding into muscle is very painful and can be dangerous. If not managed properly it can result in pressure on nerves, leading to nerve damage with paralysis and wasting of limbs.
    • Cuts of the mouth and tongue, tooth extractions and nose bleeds may ooze for long periods and require treatment.
  3. Internal bleeding

    Bleeding into the organs of the abdomen and chest is less common but may be spontaneous and serious. Abdominal pain in a boy with haemophilia always suggests a bleed.

Intracranial bleeding (within the skull) can be spontaneous or result from minor trauma, often not recognised in a child. Intracranial bleeding presents as headache, vomiting, and lethargy or irritability. Urgent clotting factor replacement is needed with internal bleeding.

4-42 When should the clinical diagnosis of haemophilia be suspected?

The diagnosis of haemophilia should be suspected if a male presents with:

  1. Large cephalhaematoma or unexplained intracranial bleeding in newborns.
  2. Excess bleeding from circumcision.
  3. Prolonged or repeated nose bleeding, and especially if it is from both nostrils.
  4. Prolonged oozing or renewed bleeding after mouth injury or tooth extraction.
  5. Easy and excessive bruising, especially if a firm subcutaneous lump is felt with the bruise.
  6. Deep muscle haematomas (collections of blood).
  7. Haemarthrosis (bleeding into joints).
  8. Prolonged oozing or renewed bleeding after surgery or trauma.

A female carrier with mild haemophilia may be suspected if she has a close male relative (brother, son or maternal uncle) with haemophilia and presents with heavy periods (menorrhagia), easy bruising or bleeding after trauma, surgery or childbirth.

It is suspected that the diagnosis of haemophilia is being missed in many cases in South Africa. Correct diagnosis of haemophilia is needed to be able to give the correct treatment and genetic counselling. A PTT test can be used to confirm that the bleeding is due to a lack of one of the clotting factors.

Blood for a PTT test must be drawn in a Vacutainer tube with a blue top and must be kept cool and reach the laboratory within a few hours.

4-43 What is the treatment of bleeding due to haemophilia?

Bleeding is rapidly controlled by giving intravenous factor VIII concentrate in haemophilia A and factor IX concentrate in haemophilia B. This is to stop further bleeding and will assist in reducing pain and lowers the risk of developing serious complications, especially chronic joint disease. For major bleeds, clotting factors should be given in hospital. However, patients over 2 years of age can often be treated at home.

Where possible, children with severe haemophilia are now being given prophylactic home therapy with clotting factor 3 times a week to prevent bleeding episodes from occurring.

Once factor VIII or IX concentrate has been given, further treatment of the problems may be needed, such as splinting during recovery, and physiotherapy to help preserve movement in the recovery phase. All operations need to take place under the cover of clotting factor replacement to ensure that there will be no excessive bleeding.

Never give aspirin or non-steroidal anti-inflammatory drugs (e.g. Voltaren and Indocid) to someone with haemophilia as these drugs increase the risk of bleeding. Haemophilia is a serious condition and must be managed in partnership with a provincial haemophilia treatment centre. Paracetamol (Panado) can safely be used for pain relief.

As soon as bleeding is suspected in someone with haemophilia, immediate treatment with the correct clotting factor concentrate must be started.

Vasopressin given nasally or intravenously increases the level of factor VIII and is useful in treating mild haemophiliacs. Tranexamic acid (Cyklokapron) can be added to the clotting factor infusion to help maintain clots in bleeding from the mouth, nose or tooth sockets.

Contact phone numbers for the Haemophilia Treatment Centres

Town Hospital Phone number
Bloemfontein Universitas 051 405 2136
Cape Town Red Cross Children Hospital 021 658 185
Cape Town Tygerberg Hospital 021 938 464
Durban Haemophilia treatment centre 031 360 3680
KwaZulu Natal   083 265 248
East London East London Health Complex 043 709 2370
Johannesburg Johannesburg 011 488 3294/86
Polokwane Dr C Sutton 082 800 6778
Port Elizabeth Livingston 041 405 9111
Umtata Prof B Ogunsanwo 084 321 2482

4-44 What genetic counselling is needed by people with haemophilia and their families?

Genetic counselling is an important part of the care of people with haemophilia, and their families. All need to be educated and informed on:

  1. The diagnosis: The clinical features and the blood tests to confirm the diagnosis.
  2. The pattern of inheritance: About 80% of males with haemophilia have a mother who is a carrier of the single gene defect on one of her X chromosomes. About 10% of these carrier mothers have mild symptoms and signs of haemophilia. The 20% of males with haemophilia, who do not have carrier mothers (no family history of bleeding), have a new mutation of their haemophilia gene.
  3. What care is needed: What haemophilia means for the affected person and what can be done to treat the various problems.
  4. Risks for future children also having haemophilia: Parents of a child with haemophilia need to understand the risk of having another child with haemophilia. They must also be told about their options and possibilities for reducing this risk and preventing the birth of another affected child. The parents also need to know of the risk that their daughters have for inheriting the abnormal gene from their mother, and therefore being a carrier. They need to understand what this will mean for the daughters.

4-45 Where can patients with haemophilia and their parents get help?

The parents, family and child with haemophilia need to be offered ongoing psychosocial support as they have problems which require lifelong care. The burden of the disorder and the care is experienced not only by the affected person, but also the family, especially parents and siblings. Support, help and reassurance in these circumstances may be obtained from:

  1. Doctors, nursing staff (especially haemophilia and nursing staff trained in genetics), genetic counsellors, physiotherapists and social workers.
  2. A patient/parent support group. These groups play a vital role in offering information and support to people affected with congenital disability. There is currently a very strong haemophilia support group in South Africa.
South African Haemophilia Foundation 021 785 7140

4-46 What is the risk for parents, with a son with haemophilia, having affected sons in future pregnancies?

If the mother is a carrier of the abnormal gene then in each of her future male pregnancies she will have a 1 in 2 (50%) chance of having a son affected with haemophilia.

If the mother is NOT a carrier of an abnormal haemophilia gene then her risk for having another son with haemophilia is very small.

With no family history of haemophilia, it has recently been shown that the mother may be a carrier, having inherited a new mutation from her elderly father. He would not have haemophilia but his sperm had a new mutation in a haemophilia gene on the X chromosome.

4-47 What is the risk for parents, with a son with haemophilia, having haemophilia carrier daughters?

The risk is 1 in 2 (50%). This is the same as the risk of having an affected son. The carrier mother has a 50/50 chance of giving her X chromosome with the abnormal gene to each of her children. This doesn’t mean that half her children will get it – they may all or none end up with it. The carrier daughters, like their mothers, have the same risks (50%) of passing the abnormal haemophilia gene on to their children.

4-48 How can you find out whether the mother of a child with haemophilia is a carrier?

If a couple has a son with haemophilia, then it is important to find out if his mother is a carrier of an abnormal haemophilia gene. There are 2 ways of finding this out:

  1. If the mother of the affected son has 1 other affected male member in her close family, such as a brother or uncle, then she is almost certainly a carrier of the abnormal gene for haemophilia.
  2. If the mother does not have such an affected close relative then she or her son with haemophilia may have a new mutation for the abnormal gene. The best way then to find out if the mother is a carrier of the abnormal gene is for her and her son to have a gene (DNA) test.

4-49 Can a father with haemophilia have affected children?

Men have one X and one Y chromosome. If a man has haemophilia he will have an abnormal haemophilia gene on his X chromosome but not on his Y chromosome (i.e. an X-linked recessive disorder). When he has children he gives his Y chromosome, with the normal non-haemophilia gene), to his sons who will get their X chromosome from their mother. Therefore, if the mother is not a carrier of an abnormal haemophilia gene, their sons will not have haemophilia.

He will give his X chromosome, with the abnormal haemophilia gene, to his daughters who will all, therefore, be carriers of the abnormal haemophilia gene.

4-50 Can haemophilia be prevented?

Yes. Because the abnormal gene for haemophilia can be tested for, a woman who is a carrier of this abnormal gene can be offered prenatal diagnosis and the option of medical termination of pregnancy. This is done after she and her partner have had genetic counselling.

It is best to provide genetic counselling and to determine whether the woman is a carrier before she falls pregnant. Prenatal diagnosis is then done early in pregnancy. This is carried out by obtaining fetal cells by amniocentesis, and testing these cells to see if they have an abnormal haemophilia gene (A or B).

The cells of the placenta can be obtained by chorionic villous biopsy, even earlier in pregnancy. The fetus and placenta have the same genes.

4-51 What special circumstances must be considered in haemophilia?

  1. If a woman is suspected of being a carrier of a haemophilia gene, the diagnosis must be confirmed or excluded before she becomes pregnant or as early in the pregnancy as possible. This allows for genetic counselling and the option of prenatal diagnosis to be offered. Ten percent of carriers may bleed heavily during a routine delivery or Caesarean section. There is also a small risk (1–2%) of a male fetus, affected with severe haemophilia, having an intracranial bleed with a vaginal delivery. Women who are known carriers, or at risk of being carriers, of an abnormal haemophilia gene should be referred to a haemophilia treatment centre before and during pregnancy.
  2. In infants suspected of having haemophilia, circumcision should not be done and they should not be given intramuscular injections. Immunisations can be given subcutaneously. They must be referred for diagnostic tests.
  3. People with haemophilia should avoid medications that may cause bleeding. The most common and important of these is aspirin and the other non-steroidal (anti-inflammatory) analgesics (pain killers). Paracetamol (Panado) can be safely used for pain relief.

Case study 1

A woman with Waardenburg syndrome delivers her first born infant who also has a white forelock. She asks whether all her infants will have the same problem.

1. What are the main features of Waardenburg syndrome?

Very blue eyes, bushy eyebrows, deafness (25% to 50%) and a white forelock (30% to 40%). Premature greying of the hair and partial albinism is common.

2. How is Waardenburg inherited?

It is usually inherited as an autosomal dominant disorder. This woman’s child has inherited her dominant gene for Waardenburg syndrome. Each of her future children will have a 50% chance of inheriting the condition.

3. Is there always a family history of the condition if a child presents with the features of Waardenburg syndrome?

No. As with many autosomal dominant disorders, the condition may appear as a new mutation and will not be inherited from a parent. About one third of patients with Waardenburg syndrome do not have a family history of the condition.

4. What is the main complication of Waardenburg syndrome?

Severe sensory deafness affecting both ears. As a result, those affected often have speech difficulties which affect their schooling and socialisation. They are not intellectually disabled.

5. How common is Waardenburg syndrome in South Africa?

It is not common (about 1 in 30 000 people). However, about 4% of people with severe deafness have the condition.

Case study 2

The first born infant of black parents has very pale skin and hair with light brown eyes. They notice that the child has abnormal eye movements and appears to have poor vision. The nurse at the local clinic tells them that they should use skin cream on the infant to prevent sunburn. The clinic does not have sun protection cream and the parents cannot afford to buy the cream.

1. What is the likely diagnosis in this infant?

The infant probably has oculocutaneous albinism (OCA) as there is lack of pigment in the skin, hair and eyes. This is the common form of albinism in southern Africa.

2. Are eye problems common in this condition?

Yes. All people with OCA have eye problems and most have poor vision. This infant has the typical jerky eye movements known as nystagmus.

3. Why is it important to use sun protection cream in these children?

Because they lack adequate pigment (melanin) to protect the skin from the ultraviolet rays of the sun, they suffer severe skin damage. Sunburn and blistering are common, resulting in rapid aging of the skin. The correct sunscreen must be used to give effective protection.

4. What skin complications should be looked for and treated?

Infections and cancer.

5. What is the life expectancy in people with oculocutaneous albinism?

Many die young as a result of skin cancer. This emphasises the importance of sun protection. The life expectancy of people with OCA in South Africa is not known.

Case study 3

A woman, whose husband has oculocutaneous albinism, visits her general practitioner as they plan to start their family. She wants to know the risk of their children also being affected. She mentions that her husband gets upset as many people think he is intellectually disabled and some children are afraid of him.

1. What is the pattern of inheritance in oculocutaneous albinism?

It is inherited as an autosomal recessive disorder. Therefore, the father must have 2 abnormal genes for melanin production (homozygous). As a result, each of his children will inherit 1 of his genes containing a single gene defect for OCA. If the mother does not have this gene, then these children will appear clinically normal but will be carriers (heterozygotes). It is possible to test the mother to see whether she is a carrier. If she is, then the couple should be sent for genetic counselling.

2. How common is oculocutaneous albinism in South Africa?

The prevalence in the black population is 1 in 3900, making it the commonest single gene disorder in the country. The prevalence in other ethnic groups is unknown.

3. Are people with oculocutaneous albinism intellectually disabled?

No. They have normal intelligence. However, their many eye problems results in poor vision and this may interfere with their schooling.

4. Why may neighbouring children be afraid of someone with oculocutaneous albinism?

Because people with oculocutaneous albinism look different. Children should not be afraid of people with OCA as they are the same as people without OCA except for their colouring. There are also many myths about people with oculocutaneous albinism. In some communities these people are believed to have special powers.

5. Can oculocutaneous albinism be prevented?

The gene for OCA is known and, therefore, prenatal diagnosis is possible. Couples at risk of having a child with OCA should receive genetic counselling, preferably before they start a family.

Case study 4

A newborn infant bleeds very heavily after circumcision. The mother reports that her uncle died of haemorrhage as a teenager after an operation, and that her brother is severely disabled due to repeated bleeds into his joints. She and her husband are well and have never had a bleeding problem.

1. How does haemophilia present clinically?

With excessive bleeding. Heavy bleeding after a circumcision is a typical way that haemophilia may present. Patients may bleed spontaneously or after trauma or surgery.

2. Is repeated bleeding into joints a common way that haemophilia presents?

Yes. Patients with severe haemophilia, who have less than 1% of the normal clotting factor activity, often bleed into big joints such as the knee, elbow or ankle. Repeated bleeds damage the joint resulting in pain and stiffness.

3. Why do people with haemophilia bleed excessively?

An inadequate amount of clotting factor VIII (in haemophilia A) or factor IX (in haemophilia B).

4. How is haemophilia inherited?

Both haemophilia A and B are inherited as X-linked recessive disorders. The females in the family carry the recessive gene on one of their X chromosome. Fifty percent of their male children will inherit the X chromosome with the abnormal gene, and as a result will have haemophilia. Both parents are usually clinically well without a bleeding problem although 10% of carrier mothers may have a mild problem.

5. How is the diagnosis of haemophilia usually confirmed?

The PTT (partial thromboplastin test) is abnormal and the concentration of either factor VIII (haemophilia A) or factor IX (haemophilia B) is low. The lower the concentration the more severe is the haemophilia. Haemophilia A is more common than haemophilia B.

6. How should a patient with a big bleed due to haemophilia be treated?

The missing clotting factor should urgently be replaced by intravenous transfusion of factor VIII for haemophilia A or factor IX for haemophilia B. This is best done by immediate consultation with a haemophilia treatment centre.

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