Birth Defects: Single gene disorders


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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

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Birth Defects: Single gene disorders

  1. 1. 4 Single gene disordersBefore you begin this unit, please take the INTRODUCTION TO SINGLEcorresponding test at the end of the book toassess your knowledge of the subject matter. You GENE DISORDERSshould redo the test after you’ve worked throughthe 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. 2. SINGLE GENE DISORDERS 67Waardenburg syndrome, oculocutaneous 4-4 How common isalbinism and haemophilia are typical examples Waardenburg syndrome?of disorders due to single gene defects Waardenburg syndrome is rare. It occurs inwith different patterns of inheritance. They about 1 in 30 000 people in all populations.illustrate many of the problems and principlesof care and management for people with single In southern Africa approximately 4% of peoplegene defects, and their families. with profound deafness have Waardenburg syndrome. This is similar to studies from other parts of the world where the prevalence ofWAARDENBURG Waardenburg syndrome amongst deaf people varies from 2 to 5%.SYNDROME 4-5 What are the main clinical features of4-2 What is Waardenburg syndrome? people with Waardenburg syndrome?Waardenburg syndrome is an inherited The main clinical features of Waardenburgdisorder that is made up of a recognisable syndrome are:collection of clinical features including 1. Very blue eyes (sapphire blue). The iris ofdeafness. It is the commonest cause of both eyes can have this extraordinary blueinherited deafness associated with a known colouring which is very noticeable in blacksyndrome in southern Africa. Africans who usually have brown eyes. In some cases only one eye or part of the iris4-3 How is Waardenburg has this colouring and the other eye orsyndrome inherited? part of the iris has the normal eye colour (heterochromia).Waardenburg syndrome is an autosomal 2. Some people with Waardenburg syndromedominant disorder: have abnormal tear ducts. This can cause1. 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. 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 childhoodWaardenburg syndrome? deafness, it is very important to diagnoseNo. Three or more of the main features their deafness as early as possiblemust be present to consider the clinical to ensure they can start early withdiagnosis. In Waardenburg syndrome, as is intervention programmes. This willfound in many other syndromes, the number ensure the best long-term outcome for theand severity of the clinical features present person’s communication ability. The earlycan vary greatly. This is called variation in clinical confirmation of the diagnosis ofexpression of the syndrome (i.e. not all the Waardenburg syndrome is also importantfeatures 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 infancydiagnosis of Waardenburg syndrome? if possible, is important so speech andYes. The gene for Waardenburg syndrome communication therapy can be startedcan 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 maynot undertaken in South Africa. benefit the infant or child should also be done as early as possible. Assessment and4-8 What are the major complications initial speech therapy need to be done atof Waardenburg syndrome? a specialised centre. On-going day-to- day speech therapy in areas far from such1. 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. 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 that4-11 What genetic counselling is parent have a 1 in 2 (50%) risk of havingneeded by parents who have a child Waardenburg syndrome. These children withwith Waardenburg syndrome? Waardenburg syndrome, when they have grown up and have their own children, willGenetic counselling is a major part of the care also have a 1 in 2 (50%) risk of passing theof people with Waardenburg syndrome and syndrome to each of their offspring. This istheir 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 Waardenburg1. The diagnosis. syndrome are normal, then the cause of2. 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 withWaardenburg syndrome need to be offeredon-going psychosocial support as with allindividuals who have a congenital disability. OCULOCUTANEOUSThere is currently no support group for ALBINISMWaardenburg syndrome in South Africa. 4-14 What is albinism? Albinism is an inherited condition. The clinical signs and symptoms of albinism are
  5. 5. 70 BIR TH DEFECTScaused by a lack of melanin in the cells of the 4-17 How common isbody. 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 accept4-15 Are there different types of albinism? intermarriage (consanguinity) as part of theirYes, there are different forms of albinism: culture (e.g. the Venda, Tswana, Pedi and1. 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 features4-16 How is oculocutaneous of oculocutaneous albinism?albinism inherited? People affected with OCA have normalOCA is inherited as an autosomal recessive physical and facial features, but have markedlycondition. Therefore, a person affected with decreased pigmentation of their skin, hair andOCA 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, easilymelanin production (i.e. one abnormal gene recognised. In White people, OCA is lessfrom each parent). As a result, the cells of obvious. The features of OCA are:an affected individual are unable to producenormal amounts of pigment and, therefore, 1. Skinthey are very pale. They have pale skin which is very sensitive to sunlight.Each parent of an affected individual has onenormal and one abnormal copy of the pigment NOTE They may have small spidery pigmentedgene (i.e. is heterozygous). Because they have patches called ephilides scattered overone normal gene that can produce melanin, their bodies, mainly on sun-exposedthey have normal pigmentation and do not areas such as the arms and 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. 6. SINGLE GENE DISORDERS 713. 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. Eyespeople 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 difficulties3. 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 well4-20 What are the major complications accepted in the community, and they in turnof oculocutaneous albinism? appear to be reasonably well adjusted. Myths1. 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. 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 whom3. 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 loss4-22 Are children with oculocutaneous of eyesight.albinism intellectually disabled? 3. Neurodevelopmental therapy, specialNo. 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 learnand young children may present with evidence and develop normally.of developmental delay. Older children may 4. Genetic counselling and psychosocialhave schooling problems due to their poor or psychosocial problems. However,if these problems are recognised early and 4-25 What skin care is needed for childrencorrectly treated with eye and visual care, early with oculocutaneous albinism?intervention programmes and counselling, It is essential for people with OCA to reducethey can be overcome. their exposure to sunlight to the greatest extent possible. As it is not possible for a person with4-23 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 wearThe 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 orHowever, due to the high risk of developing shirts, and hats with wide cancer, many unfortunately die in Sun-exposed skin, especially hands, arms andearly adult life if not correctly treated and face, should be covered with cream containingcounselled. In Tanzania and Nigeria, countries sunscreen (sun barrier creams). Cream within the tropics and close to the equator, only sun protection factor (SPF) of 30 or greater10% of people with OCA live longer than
  8. 8. SINGLE GENE DISORDERS 73must 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 inantiseptics and antibiotics if clinically indicated. their area they will have to rely on localUnfortunately 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 madeAdolescents and adults with OCA should regarding school placement. Wherebe aware of the dangers of skin cancer. They possible, children with OCA should beshould 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 schoolable to suspect and possibly diagnose cancer as may be necessary, e.g. placement in theearly as possible (e.g. sores that do not heal). In front row of the class. If, however, theiraddition they should have yearly examinations visual disability is too severe, then scholarsto 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 thewith 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 befrom 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 iswearing protective eyewear (appropriate dark usually obvious.glasses with an ultraviolet screen) and broad- 2. The cause of OCA. To explain thatbrimmed hats. In this way, further damage to OCA is a genetic disorder, inherited intheir visual disability can be minimised. an autosomal recessive manner. ThisAll people with OCA should have regular information can be used to try and dismissophthalmic or optometric assessments from the myths about why an infant with OCAinfancy. 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 managethe best chance of reasonable vision and the various problems. It is essential to stressensures that their sight is not damaged by the that every effort must be made to avoidlack 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 for4-27 What neurodevelopmental therapy, reducing the risk of having another infantcommunity-based rehabilitation and with OCA should be discussed.special education are needed for childrenwith 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. 9. 74 BIR TH DEFECTS4-29 What is the risk for normal 4-32 Who can offer psychosocial support?parents of a child with oculocutaneous Professional psychosocial support can bealbinism having other affected obtained from:children in future pregnancies? 1. Doctors, nurses (especially nurses withOCA is an autosomal recessive condition. postgraduate genetic training), geneticAs carriers of a single abnormal OCA gene, counsellors and neurodevelopmentalparents 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. Thesethe chance of either parent having an affected groups play a vital role in offeringchild is very small. information and support to people affected with congenital disability.4-30 How can oculocutaneousalbinism be prevented? There is a strong support group for people with OCA in South Africa, the AlbinismThe 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 carrythe abnormal gene. This can only be doneafter the parents receive genetic counselling.Genetic counselling is ideally undertaken HAEMOPHILIAbefore conception, or in the first 10 weeks ofthe pregnancy. The prenatal gene test is done 4-33 What is haemophilia?on fetal cells obtained by amniocentesis at 16weeks. Once the result of the prenatal test is Haemophilia is an inherited, lifelong bleedingavailable, 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 theoculocutaneous albinism, and their common form of haemophilia. Both typesfamily, need psychosocial support? present clinically as a bleeding problem.People with OCA, as with all individuals whohave a congenital disability, suffer lifelong 4-34 Why do patients withproblems which require lifelong care. The haemophilia bleed excessively?burden of the disorder is experienced not Haemophilia A is caused by a lack of normalonly by the affected person, but also the functioning clotting factor VIII (eight) whilefamily, especially parents, brothers and haemophilia B is caused by a lack of normallysisters. Mothers of newborns with OCA need functioning clotting factor IX (nine).psychosocial support to help them accept andbond with their infant, and overcome possible NOTE It is the low level of function, rather thandepression. In addition, the problem is a low concentration of the clotting factorgenetic and thus there is the possibility for the in the blood, which results in an increasedparents, the affected person and other family tendency to bleed. The single gene defectmembers 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 thesecircumstances may be a lifelong need. Haemophilia is a bleeding disorder due to the lack of a normal clotting factor.
  10. 10. SINGLE GENE DISORDERS 754-35 How is haemophilia inherited? care in many black communities, some black people with haemophilia A may notBoth types of haemophilia are inherited as X- be diagnosed and registered. Others maylinked recessive disorders. There are different die very young with severe bleeding withoutsingle gene defects on the X chromosome for the diagnosis being made. Therefore thehaemophilia 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 featuresabnormal 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 withchromosome, she will still be able to produce excessive bleeding. The bleeding may be inenough clotting factor. If she passes the X the skin and mucous membranes (bruising),chromosome containing the abnormal gene muscle, joints, internal organs or brain. Infantson to her daughter, then her daughter will usually bleed into soft tissues while older boysalso be a carrier. usually bleed into joints.If a son inherits the X chromosome with the The severity and frequency of bleeds dependshaemophilia gene from his mother, he will have on the concentration of clotting factors VIIIhaemophilia 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 factor4-36 Can females have haemophilia? VIII or IX level and they bruise easily. They usually bleed excessively followingYes. About 10% of female carriers have signs of trauma, surgery or dental care but rarelymild haemophilia. All patients with moderate have spontaneous bleeds. They usually door 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 part4-37 How common is haemophilia? of the body but some parts such as the large joints (knees, ankle and elbow) are more1. 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 circumcisionIn South Africa, haemophilia A has been found sites. Infants with severe haemophilia will bleedin 1 in 5000 white males but only 1 in 20 000 into muscles from injection or needle-stick sitesblack males. Due to poor socioeconomic or spontaneously into cephalhaematomas orconditions and inadequate access to health within the skull (intracranial bleed).
  11. 11. 76 BIR TH DEFECTS4-39 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 withYes. If haemophilia is suspected, the following haemophilia in developing countries.tests can be done to confirm the diagnosis: 2. Muscle and soft tissues1. 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 muscle2. 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) cancomplications of haemophilia? be spontaneous or result from minor trauma,These relate to the severity and site of bleeding. often not recognised in a child. IntracranialA person with haemophilia may have bleeding bleeding presents as headache, vomiting, andproblems in any part of the body. Major bleeds lethargy or irritability. Urgent clotting factorcan cause death or disability and they require replacement is needed with internal bleeding.immediate treatment with the correct clottingfactor. Minor bleeds also require treatment 4-41 When should the clinical diagnosisand, depending on their position, may cause of haemophilia be suspected?complications. The diagnosis of haemophilia should beSites 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. 12. SINGLE GENE DISORDERS 77Contact 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 24828. 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 inA female carrier with mild haemophilia hospital. However, patients over two years ofmay be suspected if she has a close male age can often be treated at home.relative (brother, son or maternal uncle) withhaemophilia and presents with heavy periods Where possible, children with severe(menorrhagia), easy bruising or bleeding after haemophilia are now being giventrauma, surgery or childbirth. prophylactic home therapy with clotting factor three times a week to prevent bleedingIt is suspected that the diagnosis of episodes from occurring.haemophilia is being missed in many cases inSouth Africa. Correct diagnosis of haemophilia Once factor VIII or IX concentrate has beenis needed to be able to give the correct given, further treatment of the problems maytreatment 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 movementto 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 andbleeding 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 mustintravenous factor VIII concentrate in be managed in partnership with a provincialhaemophilia A and factor IX concentrate in haemophilia treatment centre. Paracetamolhaemophilia B. This is to stop further bleeding (Panado) can safely be used for pain relief.and will assist in reducing pain and lowers
  13. 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 (especiallyis needed by people with haemophilia and nursing staff trainedhaemophilia 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. Thesetheir families. All need to be educated and groups play a vital role in offeringinformed on: information and support to people1. The diagnosis: The clinical features and affected with congenital disability. There the blood tests to confirm the diagnosis. is currently a very strong haemophilia2. 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 gene3. 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. 14. SINGLE GENE DISORDERS 794-46 What is the risk for parents, He will give his X chromosome, with thewith a son with haemophilia, having abnormal haemophilia gene, to his daughtershaemophilia carrier daughters? who will all, therefore, be carriers of the abnormal haemophilia gene.The risk is 1 in 2 (50%). This is the same asthe risk of having an affected son. The carriermother 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 forcarrier daughters, like their mothers, have haemophilia can be tested for, a woman who isthe same risks (50%) of passing the abnormal a carrier of this abnormal gene can be offeredhaemophilia gene on to their sons and prenatal diagnosis. This is done after she anddaughters. her partner have had genetic counselling. It is best to provide genetic counselling and4-47 How can you find out to determine whether the woman is a carrierwhether the mother of a child before she falls pregnant. Prenatal diagnosis iswith haemophilia is a carrier? then done early in pregnancy. This is carriedIf 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 ancarrier 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 be1. 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 must2. 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. Ten4-48 Can a father with haemophilia percent of carriers may bleed heavilyhave affected children? during a normal delivery or caesareanMen 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 severean abnormal haemophilia gene on his X haemophilia, having an intracranial bleedchromosome 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 shouldthe no haemophilia gene, to his sons who will be referred to a haemophilia treatmentget 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 havingabnormal haemophilia gene, their sons will haemophilia, circumcision should notnot have haemophilia. be done and they should not be given intramuscular injections. Immunisations
  15. 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 2A woman with Waardenburg syndrome The first-born infant of black parents hasdelivers 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 eyewill have the same problem. movements and appears to have poor vision. The nurse at the local clinic tells them that1. What are the main features of they should use skin cream on the infant toWaardenburg syndrome? prevent sunburn. The clinic does not have sun protection cream and the parents cannotVery blue eyes, bushy eyebrows, deafness (25 afford to buy the 50%) and a white forelock (30 to 40%).Premature greying of the hair and partialalbinism is common. 1. What is the likely diagnosis in this infant? The infant probably has oculocutaneous2. How is Waardenburg inherited? albinism (OCA) as there is lack of pigment in the skin, hair and eyes. This is the commonIt is usually inherited as an autosomal form of albinism in southern Africa.dominant disorder. This woman’s child hasinherited her dominant gene for Waardenburgsyndrome. Each of her future children will 2. Are eye problems commonhave a 50% chance of inheriting the condition. in this condition? Yes. All people with OCA have eye problems3. Is there always a family history of the and most have poor vision. This infant hascondition if a child presents with the the typical jerky eye movements known asfeatures of Waardenburg syndrome? nystagmus.No. As with many autosomal dominantdisorders, the condition may appear as a 3. Why is it important to use sunnew 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 rayshistory of the condition. of the sun, they suffer severe skin damage. Sunburn and blistering are common, resulting4. 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. 16. SINGLE GENE DISORDERS 814. What skin complications should 3. Are people with oculocutaneousbe looked for and treated? albinism intellectually disabled?Infections and cancer. No. They have normal intelligence. However, their many eye problems results in poor vision5. What is the life expectancy in people and this may interfere with their schooling.with oculocutaneous albinism? 4. Why may neighbouring childrenMany die young as a result of skin cancer. This be afraid of someone withemphasises the importance of sun protection. oculocutaneous albinism?The life expectancy of people with OCA inSouth Africa is not known. Because people with oculocutaneous albinism look different. Children should not be afraid of people with oculocutaneous albinismCASE STUDY 3 as they are normal people except for their colouring. There are also many myths aboutA woman, whose husband has oculocutaneous people with oculocutaneous albinism. In somealbinism, visits her general practitioner as they communities these people are believed to haveplan 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 oculocutaneouspeople 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 risk1. What is the pattern of inheritance of having a child with OCA should receivein oculocutaneous albinism? genetic counselling, preferably before theyIt is inherited as an autosomal recessive start a family.disorder. Therefore, the father must havetwo abnormal genes for melanin production(homozygous). Each of his children will have CASE STUDY 4a 50% chance of inheriting one of his genescontaining the single gene defect for OCA. If A newborn infant bleeds very heavily afterthe mother does not have this gene, then these circumcision. The mother reports that herchildren 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 severelyto 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 oculocutaneousalbinism in South Africa? 1. How does haemophilia present clinically?The prevalence in the black population is 1 in With excessive bleeding. Heavy bleeding3900, making it the commonest single gene after a circumcision is a typical way thatdisorder in the country. The prevalence in haemophilia may present. Patients may bleedother ethnic groups is unknown. spontaneously or after trauma or surgery.
  17. 17. 82 BIR TH DEFECTS2. Is repeated bleeding into joints a clinically well without a bleeding problemcommon way that haemophilia presents? although 10% of carrier mothers may have a mild problem.Yes. Patients with severe haemophilia, whohave less than 1% of the normal clotting factoractivity, often bleed into big joints such as the 5. How is the diagnosis ofknee, 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 either3. Why do people with haemophilia factor VIII (haemophilia A) or factorbleed excessively? IX (haemophilia B) is low. The lower the concentration the more severe is theAn inadequate amount of clotting factor haemophilia. Haemophilia A is more commonVIII (in haemophilia A) or factor IX (in than haemophilia B.haemophilia B). 6. How should a patient with a big4. How is haemophilia inherited? bleed due to haemophilia be treated?Both haemophilia A and B are inherited as X- The missing clotting factor should urgentlylinked recessive disorders. The females in the be replaced by intravenous transfusion offamily carry the recessive gene on one of their factor VIII for haemophila A or factor IXX chromosome. Fifty percent of their male for haemophilia B. This is best done bychildren will inherited the X chromosome immediate consultation with a haemophiliawith the abnormal gene, and as a result will treatment centre.have haemophilia. Both parents are usually