37

Screening for Children

This paper deals with genetic diseases and congenital abnormalities with a community health significance and the role of genetic screening as an important approach in reducing the load and consequences of genetic disease. Before considering the importance and future development of genetic screening, it is worthwhile defining the nature of genetic diseases. Several excellent reviews are available on this subject (Carter, 1969;

THE IMPORTANCE OF

Emery, 1975; Nevin, 1975).

SCREENING FOR GENETIC DISEASES

NATURE OF GENETIC DISEASE MOST HUMAN disease has at least some genetic component of variable significance in its aetiology. Genetic diseases can be classified into three general groups :(a) those associated with abnormalities of the chromosomes (chromosome abnormalities); (b) those due to a single abnormal gene or abnormal gene pairs (genic disorders); and (c) those due to the interaction of several abnormal genes, each with small detrimental effects and environmental influences (multifactorial con-

PROFESSOR N. C. NEVIN, Department o f Medical Genetics, The Queen’s University of Belfast URING THE present century there has been

dramatic

ditions). a

in the pattern of morbidity and in Western civilization due mainly to advances in obstetric care, the amelioration of social and environmental conditions, and to the effective control of infectious diseases. Genetic diseases and congenital abnormalities which have been less affected by these environmental improvements have become increasingly important. With the steady decline in infant mortality from 154 per 1,000 in 1900 to 19 per 1,000 in 1965, congenital abnormalities which, at the beginning of the century, accounted for about 5 per cent now account for some 20 per cent of infant mortality. Similarly, the introduction and increasing use of drugs and antibiotics has reduced also childhood and early adult mortality, so that many chronic diseases such as ischaemic heart disease and diabetes mellitus, have become relatively more important. Undoubtedly, many of these chronic diseases have some genetic basis. As a community health problem, genetic diseases and congenital abnormalities are important. The size of the problem is difficult to estimate accurately. A study in Northern Ireland (Stevenson, 1959) demonstrated that some 5.5 per cent of the population would be affected at some stage of their life from ill-health attributable to genetic factors. Although this study was evidently incomplete, it is interesting to note that a more recent estimation of the load of genetic disorders based on ad hoc surveys in British and allied populations arrived at a similar figure (Carter, 1977). With the increasing emphasis on prevention, medical genetics has an important role to play in this aspect of medical care. Many disorders which impose a burden on the community health services are due, at least in part, to genetic causes (Nevin, 1969). Indeed, techniques are available already which could substantially reduce this burden, but clearly an application gap exists between what is known and what is being done in the prevention of genetic disease and congenital abnormalities. On both theoretical and practical grounds, genetic diseases and congenital abnormalities cannot be eliminated totally. However, in certain situations, it would be possible to reduce their prevalence. In addition to the reduction of the prevalence, many genetic diseases and congenital abnormalities with the accompanying severe mental retardation or physical disability could be detected earlier, thus enabling earlier and more effective treatment to be instituted. ―~

mortality

change

Chromosomal abnormalities occur in at least 1 in 200 infants. One of the commonest is mongolism or Down’s syndrome, occurring in about 1 in 600 to 1 in 700 births. Most mongols have 47 chromosomes instead of 46. The additional chromosome generally arises from a failure of the pairof No. 21 chromosomes in the ovum to separate in meiosis. The genic disorders are recognised by their typical patterns of inheritance. Depending on whether the responsible gene is on the female sex chromosome (X) or on one of the 22 other pairs of chromosomes (autosomes) in each systemic cell or whether one (dominant) or both (recessive) members of the gene pair need to be abnormal to produce the disease, such diseases can be classified as X-linked dominant, X-linked recessive, autosomal dominant, and autosomal recessive. Although each of these disorders is individually rare, as a group they make a major contribution to human ill-health. Over 1,800 possible genic disorders have been documented in man (McKusick, 1975). More recently, Carter (1977) has suggested that genic disorders occur in about 10 per 1,000 livebirths. The multifactorial disorders are extremely important, accounting for many of the common diseases in man, such as diabetes mellitus and ischaemic heart disease, and also for many congential abnormalities such as spina bifida and congential heart defects. The incidence of some of the common potentially lethal or handicapping abnormalities is shown in Table I. In Northern Ireland approximately 1 in every 40 infants born has a major congenital abnormality. The above classification of genetic disorders is to some extent arbitrary, but it is useful in considering the prevention of these disorders by genetic screening. Table II illustrates the scope for the prevention of genetic disease and congenital abnormalities. DEFINITION OF GENETIC SCREENING GENETIC SCREENING is the identification of persons at risk for a genetic disorder affecting either themselves or their offspring, or relatives, before the risk is apparent. It must be emphasized that genetic screening is not diagnosis, but merely the presumptive identification of unrecognized disease. Consequently, this must be confirmed by complete clinical examination, including laboratory investigation. The subject of genetic screening has been extensively reviewed (Laurence, 1974;

Raine, 1974; Childs, 1975; Passarge, 1978).

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38 TABLEI

Incidence of the

more common

major

abnormalities in Northern

Ireland.

TABLE II

Scope for prevention of genetic disease and congenital abnormalities.

AIM OF GENETIC SCREENING GENETIC SCREENING has several aims. The detection of individuals with an abnormal genotype before they develop signs or symptoms of the disease is of value in two ways. One, is to allow an early identification of families at risk, so that the birth of further affected individuals in the family may thereby be prevented by genetic counselling. The other value is, that early treatment can prevent the development of the disease, or at least improve the prognosis. Genetic screening should be considered as a service to the individual who may have an increased risk of developing a genetic disorder or of producing an infant with a congenital abnormality. A necessary part of the screening programme should be the provision of adequate facilities for genetic counselling and facilities for follow-up and management of affected individuals. A subsidiary, but no less important, aim of genetic screening is surveillance to establish and monitor the frequency of genetic diseases and congenital abnormalities within a community. Recently, in this context the European Community (EEC) has initiated a multiregional study of the epidemiology of congenital abnormalities (Lechat, 1977). Genetic screening may be applied in a community at several levels. It may involve the whole population (mass screening) or it may affect only certain groups of the population identified because of an increased risk of a genetic disease, or of a

congenital abnormality (selective screening). POPULATION (MASS) SCREENING SCREENING OF a whole population may permit the detection of abnormal genotypes and may enable treatment to be instituted before the manifestation of symptoms and signs of the disease. Such an approach

has become routine for several severe genetic disorders such as phenylketonuria (PKU) and galactosaemia. Phenylketonuria untreated will result in severe mental retardation. Early detection and treatment with a low-phenylanine diet has altered the prognosis for this disorder. Screening for PKU is now undertaken in many countries. The introduction of population screening for PKU was not achieved without problems (Raine, 1974). This author, in a review of PKU screening indicated that ’the lesson to be learned from the experience with PKU screening is that while strict criteria must be met before embarking upon a mass screening there is almost certainly a need for limited pilot surveys which do not pay too much heed to these restrictions’. There are many other disorders of aminoacid metabolism, inherited by a recessive or X-linked mechanism, which would be amenable to population screening. In addition, certain carbohydrate disorders such as galactosaemia, and some red blood cell disorders such as glucose-6-phosphate dehydrogenase deficiency have been subject to screening. However, although it would be easy to extend such wider screening methods throughout the community, Raine (1974) has suggested that until supporting facilities to deal with the consequences of a wider screening programme, no attempt should be made to extend that limited to the recognition of PKU. The question of the possibility of population screening for cystic fibrosis of the pancreas is often raised. Cystic Fibrosis of the pancreas is a common autosomal recessive condition with an incidence of 1 in 1,800 births. However, the precise biochemical basis of the disorder remains unknown. Until a simple diagnostic test for the disease is available, any suggestion for population screening must be viewed with caution. One approach advocated as a method of screening for cystic fibrosis was the meconium test in the newborn. This was based on an increased concentration of albumin in meconium, supposedly due to diminished secretion of pancreatic proteolytic enzymes into the bowel. However, in a British study (Prosser, et al., 1974) using the meconium test found that only some 60 per cent of infants with cystic fibrosis gave positive screening results. Before population screening for cystic fibrosis is contemplated, a simple reliable test for early diagnosis is essential. Congenital hypothyroidism which is associated with mental retardation is a common disorder occurring in approximately 1 in 5,000 births. Recently, following pilot surveys in Canada and the U.S.A. recommendations have been made to establish and expand screening programmes for this condition. Although the effects of early thyroid hormone treatment (begun before one month of age) has yet to be defined, it is anticipated, however, that the results will be at least as good as those of treatment begun before three months of age, when 85 per cent of such patients had an intelligent quotient above 85 (Klein, et al., 1972). Several other metabolic diseases have been considered as possible candidates for population screening. Reliable tests for galactosaemia have been available for -several years. However, the incidence of this condition is low, about 1 in 75,000 and although early treatment will prevent fatalities, the outcome in terms of the patient’s mental achievement is not always satisfactory. The genetic hyperlipidaemias are an important group of disorders. Almost 1 per cent of the population carries a gene which will produce hyperlipidaemia. In view of the association with a significant risk of myocardial infarction in early adult life, this genotype

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39 would be suitable for population screening. However, there are difficulties in diagnosis. Motulsky & Bowman (1975) have recommended that screening for hyperlipidaemias should be limited to pilot surveys. Table III shows the incidence of some of the genetic disorders detected by population screening in the newborn. The extent of population screening for genetic disease will be determined by many factors such as the cost of screening and of subsequent treatment of affected patients, the benefits accruing to society from control of disease. Population screening will produce many unforseen difficulties, such as was seen with PKU

screening. SELECTIVE SCREENING THE RETURN from genetic screening may be increased by limiting the investigations to groups in the community with an increased risk of genetic disease. This is true, particularly in certain populations which have a high incidence of genetic disease; such as certain haemoglobin diseases in African and Asian populations and Tay-Sach’s disease in Ashkenzai Jewish populations. In Western communities an example of selective screening is for mongolism in older mothers. It is well known that the incidence of mongolism (Down’s syndrome) which is about 1 in 630 births, is dependent on - the age of mother at the time of pregnancy. The higher the maternal age the greater the risk of mongolism in the offspring. Table IV shows the effect of maternal age on mongol births. It is based on estimates of the maternal age-specific incidence and on the actual number of live babies bom to women of different ages in England and Wales in 1970. The risk that an infant born to a mother over 40 years old will be a mongol is about 1 in 60, or approximately an eleven times greater risk relative to the population. In principle it is possible to detect an affected fetus in utero sufficiently early to permit termination of the pregnancy. Samples of amniotic fluid are obtained by transabdominal amniocentesis at 15-16 weeks gestation. The amniotic fluid cells can be cultured and a subsequent chromosome analysis undertaken. Mothers aged 40 years and over are an important group for screening for mongolism. There are undoubtedly difficulties. One mam TABLE III

Genetic disorders detected

by population screening population.

of newborn

problem is the lack of facilities for laboratory diagnosis and for genetic counselling. A recent survey of severely mentally handicapped patients in Northern Ireland has revealed approximately 1 in 4 have mongolism. Indeed, some 60 per cent of these mongols have been born to mothers

over

35 years.

NEURAL TUBE DEFECTS NEURAL TUBE defects such as spina bifida and/or anencephaly are the most common congenital abnormalities in Western civilization. They are particularly common in the North and West of the United Kingdom. In Northern Ireland, 8~6 per 1,000 total births are neural tube defects (Nevin, McDonald & Walby, 1978). Parents with a family history of an infant with a neural tube defect have an increased risk of recurrence and such mothers will justify the use of transabdominal amniocentesis at 16 weeks gestation in any future pregnancy. A raised level of amniotic fluid alphafetoprotein is indicative of a fetus with an open neural tube defect and the pregnancy can be terminated. It has been estimated, however, that some 90 per cent of infants with a neural tube defect are sporadic without any history of previously affected individuals. Thus the overwhelming majority of fetuses with NTD will go undetected. The concept of screening for neural tube defects in the fetus early in pregnancy by the measurement of alphafetoprotein in the mother’s blood followed on the discovery of high concentrations of alphafetoprotein in the amniotic fluid surrounding fetuses with anencephaly and spina bifida (Brock & Scrimgeour, 1972; Nevin, Nesbitt & Thompson, 1973). Alphafetoprotein crosses the fetal membranes and is absorbed into the maternal circulation, so that a sensitive assay technique could detect these abnormalities in blood. Early in the research, it was appreciated that the estimation of maternal serum AFP would allow early detection of some, but by no means all fetuses, with a neural tube defect. Serum estimations of alphafetoprotein is only a preliminary screening test and whenever high values are found, follow-up should include ultrasonography and amniocentesis for amniotic fluid alphafetoprotein estimation. A United Kingdom Collaborative Study on Alphafetoprotein in relation to neural tube defects was set up in January 1975. Nineteen centres collaborated in this study to determine the efficiency of maternal >

alphafetoprotein measurement as a test for neural tube defects. The results were serum

screening extremely

encouraging. At 16-18 weeks of pregnancy 88 per cent of cases of anencephaly, 79 per cent of cases of open spina bifida, and 3 per cent of unaffected singleton pregnancies, had serum alphafetoprotein levels equal to or

TABLE IV Estimated age-specific incidence of Down’s syndrome number of live births and estimated number of affected infants in England and Wales, 1970. From Griffith (1973).

greater than 2.5 times the median for unaffected

singleton pregnancies. The authors concluded that screening pregnant women by measuring the concentration of alphafetoprotein in their serum was an effective method of selecting women for ultrasonography and amniocentesis so that spina bifida and anencephaly could be diagnosed in utero. Recently, Brock (1978) has reported a prospective intervention trial of serum alphafetoprotein screening for neural tube defects. Blood samples were collected from antenatal patients between the fifteenth and the sixteenth weeks of pregnancy. When the serum alphafetoprotein value lay on or above the 95th centile, but below the 98th centile, a second blood sample was taken a week later. If the value of the second blood sample remained above the 95th centile they were ..

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40 all those whose initial alphafetopabove the 98th centile, for ultrasonography and amniocentesis. The outcome of the prospective trial to end of January 1977 showed that of 6,034 samples assayed, 195 had raised serum alphafetoprotein values. Clinical examination and ultrasound investigation excluded some patients whose serum AFP became normal with a revised estimate of gestational age. Patients shown to have twins or an intrauterine death were also excluded. Of 125 amniocenteses carried out, normal alphafetoprotein values were found in the amniotic fluid in 106 cases. The remaining 19 had raised levels of amniotic fluid alphafetoprotein and termination of the pregnancy led to 12 cases of anencephaly, 6 cases of open spina bifida, and one case of exomphalos. Screening for neural tube defects, using maternal serum alphafetoprotein, has a number of disadvantages. One such disadvantage is that the upper limit of the normal range of serum alphafetoprotein is set in such a way that between 1 and 5 per cent of all normal pregnancies will initially be classified as abnormal. The majority of these will be uncomplicated normal pregnancies. Again, in the United Kingdom, where almost all mothers deliver in hospital, the time of registering at the antenatal clinic depends on the obstetric service workload. Only a small proportion of women will book between 16 and 18 weeks gestation, thus special arrangements will have to be made to capture the majority of women at the correct period of

referred, rotein

as were

values

were

gestation.

Despite these disadvantages, it is important to consider the burden of these tragic abnormalities to the family, the community, and the doctor. Understandably, this is an area which cannot be quantified. Physicians who deal with the family problems raised by spina bifida children, are in no doubt as to the justification of an efficient screening for neural tube defects, particularly in regions with a high incidence. CONCLUSIONS GENETIC SCREENING iss concerned with the identification in a population of persons with abnormal genotypes likely to be harmful to themselves or to their descendants. Screening has two main values. One, early detection before the onset of signs and symptoms will enable treatment to commence at an earlier stage, thus ameliorating the course and outcome of the disease. The second value of screening, is in allowing earlier identification of affected families so that the birth of further cases in the family may be prevented by genetic counselling and prenatal diagnosis. Genetic screening at a population level has been successfully achieved in phenylketonuria and in some other biochemical disorders. At present, mass screening is hard to justify for any condition other than phenylketonuria, with the possible exception of congenital

hypothyroidism. Screening of special groups (selective screening) has a useful place in community health care. This has been successfully undertaken in several genetic disorders such as the haemoglobin disorders in African and Asian populations and Tay-Sachs disease among Jewish populations of Ashkenazai origin. In the United Kingdom, selective genetic screening would be of value in two situations. The first would be the antenatal screening for mongolism in the fetus by amniocentesis in pregnant women 40 years old and over. These patients have a risk of a mongol infant eleven times greater than the population risk. The

second situation for selective screening is that of neural tube defects such as spina bifida and anencephaly by estimation of serum alphafetoprotein in all pregnant women.

Genetic screening is likely to have a profound impact the health of the whole population and is likely to become a wide-spread preventive medical measure. The success of genetic screening will depend on many factors including the sensitivity and reliability of the test, the benefits derived by the screening, the costs incurred by the programme, the incidence and severity of the disease, the burden of the disease to the individual, the family and the community, the attitude of the public to the aims, and also, but not least, the ethical and legal considerations. At present, there is a need to enhance the public awareness of genetic aspects of medicine and its uses in caring for individuals and families with genetic handicap. Many of the advances in medical genetics are preventive and are thus more likely to be accepted by the public if they can perceive some benefit to them and their family in accepting the care. on

REFERENCES BROCK, D. J. H. and SCRIMGEOUR, J. B. (1972). Early prenatal , 1252. diagnosis of anencephaly. Lancet, ii BROCK, D. J. H. (1978). Screening for Neural Tube Defects. In: Towards the Prevention of Fetal Malformation, Ed. J. B. Scrimgeour, pp. 37-46. Edinburgh University Press. CARTER, C. O. (1969). An ABC of Medical Genetics. London: The Lancet Ltd. CARTER, C. O. (1977). Monogenic disorders. Journal of Medical Genetics, 14, 316-320. CHILDS, B. (1975). Genetic Screening. Annual Review of Genetics, 9, 67-89. EMERY, A. E. H. (1975). Elements in Medical Genetics, 4th Ed. Edinburgh: Churchill Livingstone. GRIFFITH, G. W. (1973). The ’prevention’ of Down’s syndrome mongolism. Health Trends, 5, 59-60. KLEIN, A., MELTZER, S. and KENNY, M. D. (1972). Improved prognosis in congenital hypothyroidism treated before age of three months. Journal of Pediatrics, 81, 912. LAURENCE, K. M. (1974). Fetal malformations and abnormalities. Lancet, ii , 939-942. LECHAT, M. F. (1977). Perspectives of Epidemiology in Europe. International Journal of Epidemiology, 6, 327-328. MOLTUSKY, A. G. and BOWMAN, H. (1975). Screening for hyperlipidaemias. In: Prevention of Genetic Disease and Mental Retardation (Ed. A. Milunsky) pp. 303-16. Philadelphia London — Toronto, W. B. Saunders. McKUSICK, V. A. (1975). Mendelian Inheritance in Man. Catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes. Fourth Edition, The Johns Hopkins University Press, Baltimore. NEVIN, N. C. (1969). Genetics and Preventive Medicine, The Royal Society of Health Journal, 89, 281-285. NEVIN, N. C., NESBITT, S. and THOMPSON, W. (1973). Myelocele and alphafetoprotein in the amniotic fluid. Lancet, i, 1383. NEVIN, N. C. (1975). Aetiology of Genetic disease. In: Prevention of Handicap through Antenatal Care. Review of Research and Practice, No. 18 of The Institute for Research into Mental and Multiple —

Handicap.

NEVIN, N. C., McDONALD, J. R. and WALBY, A. L. A comparison of Neural Tube Defects identified by two independent routine recording systems for congenital malformations in Northern Ireland.

(International Journal of Epidemiology (in Press). (1978). Screening Populations for Genetic Disease. In:

PASSARGE, E.

Towards the Prevention of Fetal

Malformation, pp. 19-36.

PROSSER, R., OWEN, H., BULL, F., PARRY, B., SMERKINICK, J., GOODWIN, H. A. and DATHAN, J. (1974). Screening for cystic fibrosis

examination of meconium. Archives of Diseases of 597-601. RAINE, D. N. (1974). Inherited metabolic disease. Lancet, ii , 996998. Report of U.K. Collaborative Study on Alphafetoprotein in relation to Neural tube defects. Maternal Serum-alphafetoprotein measurement in antenatal screening for anencephaly and spina bifida in , 1323-1332, 1977. early pregnancy. Lancet, ii STEVENSON, A. C. (1959). The load of hereditary defects in human populations. Radiation Research, Supplement 1, 306-325.

by

Childhood, 49,

ThispaperwaspresentedattheHealthCongress,Bournemouth,27April, was published in the October issue.

1978. Dr. Peter Robson’s paper

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I

Screening for children: the importance of screening for genetic diseases.

37 Screening for Children This paper deals with genetic diseases and congenital abnormalities with a community health significance and the role of g...
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