Distribution and control of some genetic disorders / Bernadette Modell & Victor Bulyzhenkov

- 209 - DISTRIBUTION AND CONTROL OF SOME GENETIC DISORDERS Bernadette Modena & Victor Bulyzhenkovb One of the most important objectives of community genetics services is to reduce the frequency and clinical manifestations of severe congenital disorders, i.e. dis- orders that arise at the time of conception or during intra- uterine development, and which can cause lifelong or lethal pathology. These disorders may be roughly di- vided into congenital malformations, chromosomal dis- orders and Mendelian conditions (hereditary anaemias, PKU, cystic fibrosis, hypothyroidism). Although not all congenital disorders are of genetic or hereditary origin, they are usually considered in the context of hereditary diseases. The birth incidence of congenital disorders, including those that are trivial or relatively easily corrected, is gen- erally estimated to be in the range of 25-62 per 1 OOO live births. The incidence of severe congenital disorders that can cause early death or lifelong chronic disease ranges from about 14 per 1 OOO births in most of the more developed countries to about 43 per 1 OOO births in some less developed regions of the world (Table 1). Most infants with a severe congenital disorder (such as haemoglobinopathy, Down's syndrome, congenital mal- formation) are particularly susceptible to infections. As a result, in many parts of the world, the deaths of these children are not detected as being due to congenital dis- orders but rather are attributed to the broader category of infectious and parasitic diseases. Moreover, further reductions in infant mortality would appear to be dependent on better diagnosis and treatment of con- genital disorders and/or on reducing the number of births so affected. This article provides some data on the world distribution of several common sporadic and inherited congenital disorders (Down's syndrome, neural tube defects and haemoglobinopathies) which have a significant impact as a burden on health. • Principal Investigator. WHO Collaborating Centre for the Control of Haemoglobinopathies, London, United Kingdom. b Responsible Officer, Hereditary Diseases Programme, Division of Noncommunicable Diseases, World Health Organization, Geneva. c International Clearinghouse for Birth Defects Monitoring Systems. Annual reports 1980-1985 (ISSN 0743-5701). Available at a price of US$ 5.00 each from Dr Lisbeth B. Knudsen, Coordinator. ICBDMS, S111svinget 34, DK-2635 lsh111j, Denmark. The data on the monitoring of Down's syndrome and neural tube defects as well as other congenital malfor- mations have been collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) during the past 10-14 years. The ICBDMS is an association of programmes (now about 25) engaged in surveillance or monitoring of birth defects throughout the world. In 1986, the ICBDMS was admitted into offi- cial relations with WHO as a nongovernmental organi- zation. Down's syndrome Down's syndrome is one of the most common chromo- somal abnormalities, involving chromosome 21 in the trisomy or translocation. A large proportion of cases are liveborn and have a relatively good chance of surviving, although with varying degrees of mental retardation. Table 2 shows the rates per 10 OOO births of infants with Down· s syndrome in 1980-1985 registered in the vari- ous monitoring programmes. c There is a very wide var- iation in rates between the programmes. Aside from variable ascertainment. this can be partly explained by different maternal age composition and by different access to and utilization of prenatal diagnosis followed by selective abortion. Fig. 1 shows the large variability between the pro- grammes in the percentage of delivered women aged 35 or more and also, for each programme, a ratio indicating the deviation from the average rate of Down's syndrome that could be expected from the maternal age distribu- tion of that specific programme. Differences in maternal age distribution will cause a 50% higher Down's syn- drome rate in some programmes (Japan, Northern Ireland, South America and Spain) than in others (Czechoslovakia). Table 3 shows, for women aged 35 or more in selected programmes, the number of infants born and the number of fetuses aborted with Down's syndrome. It can be seen that in some programmes prenatal diagnosis de- tects as many or more fetuses with Down's syndrome than infants born with this disorder, whereas in other programmes only relatively few are detected. TABLE 1. ESTIMATED FREQUENCY OF CONGENITAL DISORDERS TABLEAU 1. ESTIMATION DE LA FRIEQUENCE DES TROUBLES CONGIENITAUX Type of disorder - Type de trouble Congenital malformations - Malformations congenitales . Chromosomal aberrations - Aberrations chromosomiques Mendelian disorders - Troubles mendeliens . . . .. Haemoglobinopathies - Hemoglobinopathies . . . . . . . . . . Total Wld hlth statist. quan., 41 ( 19881 All disorders. incidence per 1 OOO binhs Total des troubles, incidence pour 1 OOO naissances 17-30 4-9 4-7 0-16 25-62 Severe disorders. estimated incidence per 1 OOO binhs Troubles graves, incidence estim6e pour 1 OOO naissances 8-15 2-5 4-7 0-16 14-43 - 210 - TABLE 2. RATE PER 10 OOO BIRTHS OF INFANTS WITH DOWN'S SYNDROME REGISTERED IN VARIOUS MONITORING PROGRAMMES, 1980-1985 TABLEAU 2. TAUX POUR 10 OOO NAISSANCES DE NOURRISSONS ATTEINTS DU SYNDROME DE DOWN, ENREGISTRE DANS LE CADRE DE DIVERS PROGRAMMES DE SURVEILLANCE, 1980-1985 Down's syndrome monitoring programme 1980 Programme de surveillance du syndrome de Down Australia - Australie .. Canada ....................... Czechoslovakia - Tchecoslovaquie ........ 9.5 Denmark - Danemark ........ . . . . England & Wales - Angleterre et pays de Galles 7.3 Finland - Finlande ....... 9.5 France (Rhone-Alpes-Auvergne) France (Paris) France (Strasbourg) ..... Hungary - Hongrie . . . . . . . Israel - lsral!I .......... Italy (IPIMC) - ltalie (IPIMC) .. 14.5 Italy (Emilia-Romagna) - ltalie (Emilie-Romagne) Japan - Japan ........ . . . 11.3 Mexico - Mexique ......... New Zealand - Nouvelle-Zelande 8.0 Northern Ireland - lrlande du Nord Norway - Norvege . . ....... 9.7 South America - Amerique du Sud Spain - Espagne ......... 14.3 Sweden - Suede ....... 14.4 United States (Atlanta) - Etats-Unis (Atlanta) 11.3 United States (1 200 hospitals) - Etats-Unis (1 200 hopitaux) . . . . . . . . . . . . . . . Source: International Clearinghouse for Binh Defects Monitoring Systems. A well-known and important risk factor for Down's syn- drome is maternal age. Its impact on the prevalence at birth of Down's syndrome was demonstrated above. In fact, differences in maternal age distribution among populations seem to be a more important factor in dif- ferences in prevalence of Down's syndrome than differ- ences in the level of access to and utilization of prenatal diagnosis followed by selective abortion. However. fur- ther reduction in the number of infants born with serious handicaps-not only Down's syndrome-is possible if such prenatal diagnostic techniques are made available and accepted. 1981 1982 1983 1984 1985 Average Moyenne 11.5 11.5 11.0 12.2 11.5 5.8 5.8 7.8 7.7 9.2 6.7 8.2 6.4 8.3 9.6 9.0 10.2 8.7 7.4 8.4 7.9 7.9 6.7 7.6 8.8 8.3 9.7 8.4 9.0 8.9 6.3 12.4 10.3 11.3 10.7 10.2 9.8 13.6 12.8 10.7 11.7 11.0 8.0 10.8 10.6 10.1 7.0 5.9 8.3 7.1 12.4 15.2 13.5 13.6 12.0 14.4 12.1 10.4 12.3 12.1 14.2 14.2 7.3 14.5 6.9 9.2 11.0 10.0 13.4 9.6 13.5 8.1 11.2 9.4 6.6 8.7 11.2 10.5 9.1 14.9 14.3 14.6 15.1 15.5 14.9 11.2 9.9 9.5 8.5 13.6 10.4 14.3 15.1 16.5 15.7 15.2 15.8 12.7 13.9 15.7 14.5 13.1 12.5 14.3 12.3 13.6 13.4 13.4 8.9 10.4 7.9 9.7 10.2 8.2 9.8 9.0 Neural tube defects Neural tube defects include the specific congenital mal- formations varying from anencephaly to different forms of spina bifida. Table 4 presents, for the various partici- pating monitoring programmes, the annual number of infants registered with anencephaly, spina bifida and encephalocele, respectively. As can be seen from this table, there are very marked variations in rates. These are partly due to genetic differences. For example, it is well-known. and can also be seen in the table, that regions with a predominantly Anglo-Saxon population TABLE 3. NUMBER OF INFANTS BORN WITH DOWN'S SYNDROME, NUMBER OF ABORTED FETUSES WITH THIS CONDITION, AND RATIO BETWEEN NUMBER OF INFANTS AND NUMBER OF ABORTED FETUSES (RESTRICTED TO MATERNAL AGE OF 35 OR MORE) TABLEAU 3. NOMBRE DE NOUVEAU-NES ATTEINTS DU SYNDROME DE DOWN, NOMBRE DE FCETUS AVORTES ATTEINTS DE CETTE AFFECTION ET RAPPORT ENTRE LE NOMBRE DE NOUVEAU-NES ET LE NOMBRE DE FCETUS AVORTES (LIMITE AUX MlRES AGEES DE 35 ANS OU PLUS) Monitoring programme Programme de surveillance Australia - Australie . . . . . . . . . . . . Czechoslovakia - Tchecoslovaquie Denmark - Danemark . . . . . . . . . . . England & Wales - Angleterre et pays de Galles ..... Finland - Finlande . . . . . . . France (Rhone-Alpes-Auvergne) ... France (Paris) . . . . . . . . . . . . . France (Strasbourg) . . . . . . . . . . Italy (Emilia-Romagna) - ltalie (Emilie- Romagne) . . . . ....... . Northern Ireland - lrlande du Nord Sweden - Suede . . . . . . . . . . . Total infants born Total de nouveau-n6s 17 985 5 171 4 187 52300 8 162 6 910 4 552 810 2000 3015 11 487 Source: International Clearinghouse for Binh Defects Monitoring Systems. Infants with Down·s syndrome Nouveau-n,s atteints du syndrome de Down 76 17 2 117 27 26 15 3 13 21 46 Fetuses with Down·s syndrome Fa,tus atteints du syndrome de Down 31 11 21 138 26 18 27 3 1 6 45 Ratio Rappon 2.5 1.5 0.1 0.8 1.0 1.4 0.6 1.0 13.0 3.5 1.0 Rapp. trimest. statist. senit. mond., 41 (19881 211 - FIG. 1 MATERNAL AGE DISTRIBUTION IN RELATION TO RATE OF DOWN'S SYNDROME IN 19 MONITORING PROGRAMMES DISTRIBUTION DES AGES DES M~RES PAR RAPPORT AU TAUX D'INCIDENCE DU SYNDROME DE DOWN DANS 19 PROGRAMMES DE SURVEILLANCE A. Deviation from the average rate of Down's syndrome that could be expected from the maternal age distribution of each programme Ecart par rapport au taux d'incidence moyen du syndrome de Down auquel on peut s'attendre compte tenu de la distribution des ages des meres dans chaque programme c 0 0. 0. .. a: I Q ~ 0 0 0 ___ o ______ ..,.o ----··- 0 0 0 0 0 0 0 0 0 0 0 .5 L---'---L--'----'---'-__j____j __ ~-~-~--'---'---'---'---'---'---'---'---'--' B. Percentage of women delivered at age 35 or more, per programme Pourcentage de femmes ayant accouche a 35 ans ou plus, par programme 10~~~~~~~~--~~~· "' c: .. + "' M "' C> .. g f:! :, ~ I "' iii "' 8 6 ; 4 "' M 8, .. E "' f:! "' 0. 2 0 .'!! " ·~ '!! a lii .. > :, 0 <( .; I 0 u . !!! .., .J:. '!! u I-lii :, I <( .. .. .. > .Q "' 0 .J:. u l!l u Wld hlth statist. quan., 41 ( 1988) "" I "' "' oi .; iii "' "C "' c: c: "i E "' .; e> !l! ~ " .; (!) c: "' c: 3: " ..;: > "' .. "C :, u 0 <( ,II "' c: I > .. ~ "C .. "C "' .... "" c: 0. c: 0. ~; .. iii 'i: < E ~ ~ ..;: " c: c: "' :;; '° 0 .!! .J:. s. C> c: "' <( u c: .t a> cr ii: c: "' "' 1:! " "C "' 0 :, "C C> :, c: :5 ::;; w 0. g c: 0 .., VJ C> i .. .. z i:: .. 0 ~ " :, .Q ..., "' 'iii :, 0 "C 0. "' ::;; N "C z "' ~ .'!! .!!! .!l " "' w ~ I :, ~ ~ c: .; "C g .. c: 0. 0 > ~ > ~ c: " .. u :, .. E ... u ..., ·~ 0 ;:: c: cr ii: " z 0 <( ~ .t w ::;; ::;; i I "C z I ~ "C c: .. > c: .. .!! > ~ !l! ] iii .. ~ "' c: E N :;; <( ;:: .J:. .J:. " c '5 z 0 z 0 VJ Country - Pays "' .; "C ... E :, !l! VJ ~ I "' c: i: "' "C ;) " .. ;:: :;; VJ w .; E !l! ~ "' "' :;; <ii "C l!l i: ;) ~ °' "' ., 0 l: ?:: - 212 - TABLE 4. RATE PER 10 OOO BIRTHS OF INFANTS WITH NEURAL TUBE DEFECTS REGISTERED IN VARIOUS MONITORING PROGRAMMES, 1980-1985 TABLEAU 4. TAUX POUR 10 OOO NAISSANCES DE NOUVEAU-NIES PRESENTANT UNE ANOMALIE DU TUBE NEURAL, ENREGISTRE DANS LE CADRE DE DIVERS PROGRAMMES DE SURVEILLANCE, 1980-1985 Monitoring programme Programme de surveillance Australia - Australie . . . . . . . . Canada ............... . China - Chine . . . . . . . Czechoslovakia - Tchecoslovaquie Denmark - Danemark . . . . . . . . . England & Wales - Angleterre et Galles Finland - Finlande France (Rhl>ne-Alpes-Auvergne) France (Paris) France (Strasbourg) Hungary - Hongrie . . . Israel - Israel Italy (IPIMC) - ltalie (IPIMC) . . . . . . Italy (Emilia-Romagna) - ltalie (Emilie-Romagne) Japan - Japan . . . . . . . . . . Mexico - Mexique . . . . . . . . . New Zealand - Nouvelle-Zelande Northern Ireland - lrlande du Nord Norway - Norvege South America - Amerique du Sud Spain - Espagne . . . . . . . . . . Sweden - Suede . . . . . . . . . . . . . . . United States (Atlanta) - Etats-Unis (Atlanta) United States (1 200 hospitals) - Etats-Unis (1 200 hl>pitaux) . . . . . . . . . . . . . . . Australia - Australie Canada China - Chine . . . . Czechoslovakia - Tchecoslovaquie Denmark - Danemark . . . . . . . England & Wales - Angleterre et Galles Finland - Finlande . . . . . . . France (Rhl>ne-Alpes-Auvergne) France (Paris) . . . . . France (Strasbourg) . . . . . . . Hungary - Hongrie . . . . . . . . Israel - Israel . . . . . . . . . . . Italy (IPIMC) - ltalie (IPIMC) . . . . . . . . . Italy (Emilia-Romagna) - ltalie (Emilie-Romagne) Japan - Japan . . . . . . . . . . Mexico - Mexique . . . . . . . . . . . New Zealand - Nouvelle-Zelande . . . Northern Ireland - lrlande du Nord Norway - Norvege . . . . . . . . . South America - Amerique du Sud . . Spain - Espagne . . . . . . . . . . Sweden - Suede . . . . . . . . . . . . United States (Atlanta) - Etats-Unis (Atlanta) United States (1 200 hospitals) - Etats-Unis (1 200 Mpitaux) . . . . . . . . . . . . . . . Australia - Australie . . . . . . . . Canada .............. . China - Chine . . . . . . . Czechoslovakia - Tchecoslovaquie Denmark - Danemark England & Wales - Angleterre et Galles Finland - Finlande . . . . . . . . . . . . France (Rhl>ne-Alpes-Auvergne) France (Paris) . . . . . France (Strasbourg) . . . . . . . Hungary - Hongrie . . . . . . . . Israel - Israel . . . . . . . . . . . Italy (IPIMC) - ltalie (IPIMC) . . . . . . Italy (Emilia-Romagna) - ltalie (Emilie-Romagne) Japan - Japan . . . . . . . . . . . . Mexico - Mexique . . . . . . . . . New Zealand - Nouvelle-Zelande Northern Ireland - lrlande du Nord Norway - Norvege . . . . . . . . . South America - Amerique du Sud Spain - Espagne . . . . . . . . . . Sweden - Suede . . . . . . . . . United States (Atlanta) - Etats-Unis (Atlanta) United States (1 200 hospitals) - Etats-Unis (1 200 hl>pitaux) . . . . . . . . . . . . . . . 1980 1981 1982 Anencephaly - Anencephalie 5.9 5.7 4.7 4.8 3.4 3.0 5.2 3.0 0.4 4.9 3.3 3.7 5.0 4.0 6.9 16.6 3.5 1.8 3.4 1.8 5.8 3.3 3.5 2.4 3.9 2.2 1.2 6.0 6.7 3.7 5.2 3.9 5.8 17.4 4.5 4.0 3.1 1.2 3.0 Spina bifida 7.3 4.3 3.5 11.4 1.7 4.1 9.9 6.7 4.7 2.5 12.9 12.6 20.1 6.6 5.3 4.3 3.9 7.7 5.2 5.4 3.4 2.6 10.4 2.3 2.9 11.0 9.0 7.5 0.5 11.1 10.9 20.3 5.7 8.6 3.2 5.2 5.6 2.7 2.5 2.6 2.6 0.9 1.5 7.7 7.7 2.7 8.3 4.5 7.0 12.9 2.9 6.6 2.9 1.5 2.5 3.3 7.7 6.3 3.7 3.0 8.1 1.8 3.7 4.1 4.4 12.0 9.9 5.3 2.1 9.5 10.4 20.6 6.4 5.2 4.1 4.5 5.0 4.8 Encephalocele - Encephalocele Source: International Clearinghouse for Birth Defects Monitoring Systems. 1983 5.8 4.7 1.9 1.2 1.8 0.6 1.4 1.3 3.2 6.3 9.0 2.9 11. 1 3.8 3.8 9.1 3.6 5.7 2.3 1.8 3.2 3.0 8.0 6.7 3.6 4.5 6.7 2.8 3.2 4.5 5.6 11.2 3.4 2.9 3.2 10.4 11.5 15.7 4.8 5.5 3.9 4.5 7.5 4.7 1.6 0.9 0.8 1.2 0.8 0.4 0.7 1.3 1.1 0.7 0.5 1.6 0.8 1.5 0.8 3.5 1.3 0.9 2.1 1.2 1984 4.3 3.3 1.2 1.4 1.1 1. 1 0.8 7.0 4.0 5.9 1.7 4.6 3.0 2.8 4.7 2.0 7.2 2.8 1.1 3.8 2.6 6.6 3.3 3.8 5.9 1.8 3.7 1.8 7.0 9.8 11.7 4.0 2.6 13.2 10.6 17.2 5.3 6.9 4.7 4.0 6.5 4.9 1.6 0.6 0.7 0.3 1.3 1.2 1.0 1.0 1.8 0.4 1.8 0.6 2.1 0.8 0.4 1.7 1.2 1985 5.1 5.4 1.5 1.1 0.9 1. 1 0.8 2.3 4.0 3.4 1.9 0.4 4.2 1.8 3.5 7.9 4.3 6.3 2.4 0.7 2.6 2.7 6.5 4.4 3.4 3.5 5.3 1.6 4.5 1.7 3.8 10.2 5.6 4.4 3.3 3.7 10.2 7.2 11.1 4.7 7.1 5.0 5.5 6.1 4.5 1.2 1.4 0.9 0.7 0.6 0.2 0.5 0.7 0.8 0.6 1.1 0.4 2.1 1.4 0.8 1.4 1.9 1.4 1.0 1.0 2.6 1.0 Average Moyenne 5.3 5.0 5.4 2.8 1.9 2.6 1.7 1.0 0.9 3.1 5.5 5.6 2.5 0.4 6.4 3.6 4.9 11.5 3.5 5.9 2.8 1.3 3.5 3.0 7.2 6.4 4.4 3.6 3.5 8.0 2.0 3.7 3.0 5.2 10.7 7.4 4.4 3.3 2.4 11.3 10.5 17.5 5.6 6.7 4.2 4.6 6.4 4.9 1.5 0.9 1.4 0.8 1.0 0.7 0.3 0.6 1.1 0.8 0.0 1.0 0.9 0.4 1.2 1.6 0.7 1.6 1.1 2.3 1.1 0.8 2.1 1.1 Rapp. trimest. statist. sanit. mond., 41 (19881 - 213 - generally have high rates. Non-genetic differences be- tween the populations may also exist. A third source of variation is the level of accessibility to prenatal diagnosis followed by selective abortion. Finally, different defini- tions of stillbirths (especially important for anencephaly) and differences in ascertainment contribute to the varia- tion. The populations studied represent many different types of societies, from highly industrialized countries to devel- oping countries. Not only reproductive patterns but also other risk factors may vary considerably. An example is maternal work during pregnancy and the possible occu- pational risk factors to which pregnant women may be exposed. Long-term trends have repeatedly been observed in the prevalence at birth of neural tube defects, e.g. spina bif- ida. Fig. 2 shows the downward trend in Clearinghouse datac for anencephaly and, to a less marked degree, for spina bifida. It is possible that the marked short-term decrease of anencephaly is rather due to an increasing use of prenatal diagnosis than to actual changes in the prevalence of the malformation. It should be noted, how- ever, that a downward trend of neural tube defects was noticed in many countries long before prenatal diagnosis became so common that it could have an impact. Table 5 compares the number of infants born with a neural tube defect in 1984 and the number of aborted fetuses with such defects in some programmes with information of this kind. The differences in proportion between infants born and fetuses aborted may, to some extent, be due to differences in ascertainment of aborted fetuses but may also illustrate differences in access to prenatal diagnosis. Haemoglobinopathies Haemoglobinopathies are the commonest lethal inher- ited diseases. They include the thalassaemias (the a and the /1-thalassaemias and the Hb E/B-thalassaemia) and the sickling syndromes (homozygous sickle-cell anae- mia, Hb S/C disease and HbS/B-thalassaemia). Haemo- globinopathies are inherited through symptomless car- riers (heterozygotes) in a Mendelian recessive manner; when two carriers mate they have a 1 :4 chance in each pregnancy of producing an affected (homozygous) child. Incidence and distribution Population surveys have been done in most countries where haemoglobinopathies are indigenous. In many other areas (for example, much of South America and North-West Europe), their incidence can be calculated from the ethnic composition of the population, so that it is now possible to provide an estimate of their frequency for almost every country. The approximate global num- bers involved are given in Table 6. FIG. 2 2 1.5 .5 ANENCEPHALV RATIOS OF ANNUAL MALFORMATION RATES DIVIDED BY THE AVERAGE RATE FOR THE WHOLE PERIOD 1980-1985• 0 0 0 00 0 0 0 oO 0 0 0 0 QUOTIENT DES TAUX D'ANENCIEPHALIE ANNUELS PAR LE TAUX MOVEN POUR L'ENSEMBLE DE LA PIERIODE 1980-19858 0 00 0 0 0 go oo 0 0 oO 0 0 0 0 0 Anencephaly - Anenc~phalie 0 0 Oo 0 0 0 0 oo oO 0 0 0 0 a Each programme is marked by a dot and the means for each year are connected by a solid line -Les points indiquent des programmes et les mayennes pour chaque ann~e sont reliees par une ligne continue. Source International Clearinghouse for B1nh Defects Monitoring Systems. Wld hlth statist. quan .• 41 ( 1988) - 214 - TABLE 5. NUMBER OF INFANTS BORN WITH NEURAL TUBE DEFECTS, NUMBER OF ABORTED FETUSES WITH SUCH DEFECTS AND RA TIO BETWEEN NUMBER OF INFANTS AND NUMBER OF ABORTED FETUSES TABLEAU 5. NOMBRE DE NOUVEAU-NES PRESENTANT DES ANOMALIES DU TUBE NEURAL, NOMBRE DE FCETUS AVORTES PRESENTANT DE TELLES ANOMALIES ET RAPPORT ENTRE LE NOMBRE DE NOUVEAU-NIES ET LE NOMBRE DE F<ETUS AVORTES PRESENTANT DE TELLES ANOMALIES Monitoring programme Infants born Aborted fetuses Ratio Programme de surveillance Nouveau-n6s Fcetus avort;\s Rapport Australia - Australie ..... 33a 6 5.5 Denmark - Danemark 26 16 1.7 Finland - Finlande . . . . . . . 21 7 3.0 France (Rhclne-Alpes-Auvergne) 42 18 2.3 France (Paris) .. 15 38 0.4 France (Strasbourg) 5 11 0.5 Norway - Norvege 40 12 3.3 Sweden - Suede 52 40 1.3 a Estimate - Estimation. Source: International Clearinghouse for Birth Defects Monitoring Systems. TABLE 6. GLOBAL NUMBERS OF CARRIERS OF HAEMOGLOBINOPATHIES TABLEAU 6. NOMBRE DE PORTEURS D'HEMOGLOBINOPATHIES DANS LE MONDE % of the population heterozygous for : Population % de la population htlttlrozygote pour : Total% of population in millions Region - Region Population Sickle-cell Pourcentage traits p thalassaemia traits a· thalassaemia en millions total de d'habitants HbS and C P thalass6mie trait la population Dr6panocytose Pthal HbE a· thalassemie HbSet C Africa - Afrique North - Nord . . 116 0.3-2.3 1-4 4.8 North-East - Nord-Est 38 0 0-1 East - Est 82 1-40 11.2 South - Sud ...... 34 Islands - lies . . 11 1.5-20 8.9 Sub-Saharan - Sub-saharienne 212 2-40 0-4 23.3 Total Africa - Total Afrique 493 0-40 0-4 13.3 Americas - Ameriques North - Nord . . 257 1.6 1.2 Central - Centre ... 97 0.6 0.6 South - Sud .. 252 0-5 3.6 Caribbean - Caraibes 31 3-12 1-2 9.7 Total Americas - Total Am6riques ....... 637 0-12 1-2 2.5 Asia - Asie North-West - Nord-Quest 161 0-20 1-16 3.8 South - Sud ...... 924 0-40 1-13 0-10 4.2 North-East - Nord-Est 915 South-East - Sud-Est 663 1-10 0-40 (1.9) 11.6 Total Asia - Total Asia 2663 0-40 0-16 0-40 0-4 4.6 Europe North-West - Nord-Quest 237 0.3 North-East - Nord-Est 79 South - Sud 172 0-25 1-15 2.4 USSR - URSS ..... 270 0-15 1.7 Total Europe - Total Europe 758 0-25 0-15 1.3 Oceania .............. 28 1. 1 Global total - Total mondial 4579 4.6 Number of heterozygotes (millions) Nombre d·heterozygotes (en millions) 5.53 0.33 9.15 1.0 49.4 65.4 3.0 0.6 9.1 3.0 15.7 6.1 39.0 76.6 121.7 0.72 4.13 4.65 9.5 0.3 212.6 Rapp. trimest. statist. sanit. mond .• 41 ( 1988) - 215 - FIG. 3 SPINA BIFIDA RATIOS OF ANNUAL MALFORMATION RATES DIVIDED BY THE AVERAGE RATE FOR THE WHOLE PERIOD 1980-19858 QUOTIENT DES TAUX ANNUELS DE SPINA BIFIDA PAR LES TAUX MOYENS POUR L'ENSEMBLE DE LA PIERIODE 1980-1985• l 0 Sp,na b,f,da 1.5 ~ r i 0 0 0 0 0 0 00 0 0 Oo i Oo 00 I 0 oO ~ 88 L 8g 00 j 0 oO 0 do ·- ~ -----o---- .... . ·88= ___ - -----00----0 ou 0 0 0 og So ~ I o~o--:::=:::::::::~:::::::::~,,,,,.--~~-----------~~;.;;;.._:..;,;.;;.;.:,__:;;.;;_~li:::.:=:....:__...:.:=~ r---:: ~ J ~ oo 0 0 0 00 0 Oo 0 0 00 0 0 00 0 0 00 0 0 o ~I __ __,_ ______ _._ _____ ~~-------1 ____ _ 1 1984 _ ___ _L_ 1980 1981 1982 1983 1985 a Each programme is marked by a dot and the means for each year are connected by a soltd line - Les points indiquent des programmes et les moyennes pour chaque annee sont rehees par une ligne continue. Source lnterna11onal Clearinghouse for Birth Defects Monitoring Systems. At present about 190 million people (4% of the world population) carry a potentially pathological haemoglobi- nopathy gene. More than half are thalassaemia genes, but globally sickle-cell disease is more common than the thalassaemia syndromes, because of the very high den- sity of sickle-cell carriers in Africa and the affected parts of lndia.d Surveys give the carrier frequency, but for public health purposes it is appropriate to calculate the birth rate per 1 OOO of infants with a major (i.e. usually lethal) haemo- globinopathy. Fig. 3 and Table 7 give the results ofthese calculations. At present, each year about 240 OOO in- fants are born with major haemoglobinopathies, about 20% with thalassaemia syndromes and about 80% with sickle-cell disease. Allowance must be made for the fol- lowing factors: 1. Population size and growth. Though at present about 4% of the world population are carriers of haemo- globinopathies, the final figure may be closer to 6-7% because of future differential growth of the populations with the highest incidence. 2. Population movements. Migration has introduced the haemoglobinopathies into many areas where they d World Health Organization. Update of the progress of haemoglobi- nopathies control (Milan 1984/Bangkok 1985). Report of the Third and Fourth annual meetings of the WHO Working Group on the Community Control of Hereditary Anaemias. (Document HMG/WG/85.8). Wld hlth statist. quart., 41 (19881 were not originally endemic. In the United States of America 10% of the population is at risk for sickle-cell disease, and in North-West Europe between 2% and 9% of most populations now belong to ethnic minorities at risk for the haemoglobinopathies. The movement and mixing of populations in many countries will ultimately reduce the homozygote birth rate by dispersing groups with a high carrier frequency among larger populations with a lower frequency. However, in South-East Asian countries where the relatively benign HbE gene is preva- lent in some parts of the population and P-thalassaemia in others, population mixing will substantially increase the amount of genetic pathology. 3. The frequency of consanguinity. The positive con- vention of consanguineous marriage that prevails in large parts of the world increases the homozygote birth rate relative to the heterozygote frequency. 4. The effects of improved primary health care. The haemoglobinopathies are common because the carriers are protected against death from falciparum malaria. Where malaria is common, relatively more of the off- spring of carriers than of non-carriers survive to repro- ductive age, so the frequency of the genes tends to reflect the present or past prevalence of malaria. Where malaria is prevalent, many homozygotes die from ma- laria in infancy, and once malaria is brought under con- trol, the haemoglobinopathies emerge as an important cause of chronic disease. - 216 - TABLE 7. GLOBAL ANNUAL BIRTHS OF INFANTS WITH MAJOR HAEMOGLOBINOPATHIES TABLEAU 7. NOMBRE ANNUEL DE NAISSANCES D'ENFANTS ATTEINTS D'HEMOGLOBINOPATHIES MAJEURES DANS LE MONDE Affected Thousands of annual births of homozygotes with : births Milliers de naissances par an d'homozygotes per 1 OOO porteurs de Region - Region Naissance Total d'enfants a· thalassaemia atteints SS SC SIP thal Pthal HbE/thal a· thalasstlmie pour 1 OOO a· a• HbH (000) Africa - A frique North - Nord 1.17 (--1.6--] 1.17 3.0 5.77 North-East - Nord-Est 0.02 East - Est .. 3.5 13.63 South - Sud .... Islands - lies 2.3 1.05 Sub-Saharan - Sub-saharienne 14.0 110.4 Total Africa - Total Afrique 9.2 126.7 Americas - Ameriques North - Nord 0.25 0.57 Central - Centre 0.04 South - Sud 0.51 2.28 Caribbean - Cara"tbes 2.9 1.47 Total Americas - Total Ameriques 0.47 4.3 Asia - Asie North-West - Nord-Quest 1.28 4.0 South - Sud .. 0.94 14.81 North-East - Nord-Est South-East - Sud-Est . 1.23 Total Asia - Total Asie 1.15 18.8 Europe North-West - Nord-Quest 0.13 0.28 North-East - Nord-Est South - Sud 0.28 USSR - URSS 0.08 Total Europe 0.16 0.3 Oceania - Oceanie 0.21 Global total - Total mondial 2.1 150.1 5. The impact of prevention programmes. In Southern Europe and in the Mediterranean area, large-scale screening and counselling programmes have greatly re- duced the birth rate of infants with thalassaemia major, and the disease is actually disappearing from some areas (Fig. 4). The clinical and financial burden of the disorders is so great that it is highly cost-effective to introduce a control programme along these lines, especially in developing countries. e Control of haemoglobinopathies By using relatively cheap and simple blood tests, it is possible to detect carriers. Consequently. the haemo- globinopathies can be prevented at the community level by population information, carrier screening and genetic • World Health Organization. Community approaches to the control of hereditary diseases. Report of a WHO Advisory Group. October 1985. (Document HDP/WG/85.10). 0.04 0.04 13.63 0.01 1.06 31.6 142.0 31.6 >1.2 >3.1 162.6 0.26 0.13 0.09 1.05 1.04 0.5 0.4 4.22 0.67 0.32 2.48 2.0 0.95 0.5 7.9 1.43 3.1 8.52 14.81 1.84 31.46 7.06 15.3 7.23-16.5 46.1 1.43 25.0 17.1 23.73 86.1 0.12 0.40 0.9 0.9 0.87 0.9 1.89 2.2 0.1 0.1 33.6 3.6 30.6 >17.1 23.7 258.7 counselling, and the offer of prenatal diagnosis with sel- ective abortion of affected pregnancies to couples of carriers. Most couples at risk for thalassaemia choose prenatal diagnosis and selective abortion of affected pregnancies in order to ensure a healthy family, thus many births of affected children can be avoided when screening and counselling are provided. The recent intro- duction of prenatal diagnosis at around nine weeks' ges- tation has considerably increased the acceptability of this approach to prevention. In France and in the United Kingdom about 50% of counselled couples at risk for sickle-cell disease accept prenatal diagnosis. It is there- fore clear that information. counselling and choice should also be provided for sickle-cell disease, and would also be expected to make a considerable impact on its incidence. Acknowlegements The authors wish to express their gratitude to Dr E. Knudsen and Professor B. Kallen, members of the ICBDMS, for their kind assistance in providing the data presented in this article. Rapp. trimest. statist. sanit. mond .. 41 (1988) - 217 - FIG. 4 FALL IN THE BIRTH RATE OF INFANTS WITH THALASSAEMIA MAJOR ASSOCIATED WITH SEVERAL THALASSAEMIA CONTROL PROGRAMMES CHUTE DU TAUX DE NATALITE DE NOUVEAU-NES ATTEINTS DE THALASSEMIE MAJEURE ASSOCIEE A DIVERS PROGRAMMES DE LUTTE CONTRE LA THALASSEMIE ~ :, ., .... E ., E ,., ~.,, 0.,, ·;-12 E1 "' -H ., :, ~E .,, "' "' -~~ .c 'E .!: c. 3:!!J .,, c .c "' t- ·- c .a " o~ ~~ "'c -"' c.,, ~ ·~ ., c c.., -0 -0 ~:, "-0 "c c.., ><::: w"' ., "' "' E "' " 5 0 0.. 100 90 80 70 60 50 40 30 20 10 0 1970 1972 ------, -·,: ---, I L--- ----, . :1: ••••.•• . . L-., ~ .. ~·~·l············· : . . : United Kingdom - Aoyaume-Uni ..... ~~~~~~ ..... ~ ... ----, •.............. . 1974 I I I I I I I ............... Greece - Grece I L---·-·1 Sardinia - , I 1.--------, i._ ~~~n.:... . J I l Cyprus - Chypre I I L---, Ferrara - Ferrare I I I I L----, ---------. L---, I L--- 1976 1978 1980 1982 1984 Year - Annee WHO 851710 Source: WHO/OMS Document HMG/WG/85.8. MAP 1. WORLD DISTRIBUTION OF THE HAEMOGLOBINOPATHIES (THALASSAEMIAS AND SICKLE-CELL DISEASE), 1985 CARTE 1. REPARTITION DES HEMOGLOBINOPATHIES DANS LE MONDE (THALASSEMIE ET DREPANOCYTOSE), 1985 / Births per 1 OOO of infants with a major haemoglobinopathy Naissances pour 1 OOO nouveau-n8s atteints d'h6moglobinopathie majeure D < 0.1 D 0.1 - 0.19 ~ 0.2-0.99 - 1-4.9 - 5-9.9 - 10 - 18.9 - >19 Wld hlth statist. quart., 41 ( 1988) 7---- / ./ \ / ' I I I - 218 - SUMMARY The health burden of genetic disorders varies between ethnic groups within the same country or between coun- tries to a large extent because of genotypic differences at the population level. Genetic services should recog- nize this variability in need and be developed within the traditional context of medical care. All practical ap- proaches require a sound epidemiological basis and underline the importance of early diagnosis for both pre- vention and treatment. Effective control is now possible for some Mendelian conditions and some congenital malformations and should be incorporated into general health care. The development of genetic services within any country depends on the optimal utilization of avail- able resources, both financial and intellectual. RESUME Distribution de certains troubles genetiques et mesures de lutte L'impact des troubles genetiques varie d'un pays a l'au- tre ou a l'interieur d'un m~me pays d'un groupe ethnique a l'autre, en grande partie en raison de differences geno- typiques au niveau de la population. Les services gene- tiques doivent reconnaitre cette variabilite des besoins et se developper dans le cadre du contexte traditionnel des soins medicaux. Toutes les approches pratiques supposent une base epidemiologique solide et souli- gnent !'importance d'un diagnostic precoce pour la pre- vention et le traitement. Une lutte efficace est mainte- nant possible contre certaines maladies transmises se- lon le mode mendelien et contre certaines anomalies congenitales et devrait ~tre incorporee dans les soins de sante generaux. La mise sur pied de services genetiques dans un pays depend de !'utilisation optimale des res- sources disponibles aussi bien financieres qu'intellec- tuelles. Rapp. trimest. statist. sanit. mond .. 41 (19881