Hereditary disorders in the Eastern Mediterranean Region.

Hereditary disorders in the Eastern Mediterranean Region H. Hamamy1 & A. Alwan2 Hereditary diseases and congenital malformations have been reported to affect 2-5% of all live births. Available evidence suggests that genetic disorders are equally important also in countries of the East- ern Mediterranean Region. Considerable achievements have been made over the last two decades in controlling communicable diseases in the region. Concurrently, there has been a mounting awareness of the increasing importance of hereditary disorders. Certain genetically determined diseases such as the haemoglobinopathies and enzymopathies are extremely common in the region and the need to initiate public health measures for their control is increasingly being recognized. The following factors may contribute to the elevated prevalence of genetically determined disorders: the high consanguinity rates; the high frequency of haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency; the trend of continuing to bear children up to menopause; the general lack of public awareness about genetic diseases; and the dearth of genetic services in the region. These and some other related issues are discussed in detail in this review article. Introduction Hereditary diseases and congenital malformations have been reported to affect 2-5% of all live births; they account for up to 30% of paediatric hospital admissions, and cause about half of childhood deaths in developed countries (1). Available evidence sug- gests that genetic disorders are important also in countries of the Eastern Mediterranean Region. For example, a survey of paediatric inpatients in a Saudi Arabian hospital from 1985 to 1989 revealed that almost 16% had congenital anomalies and genetical- ly determined disorders (2). Furthermore, of paedi- atric deaths in 1985 in a Kuwaiti hospital, 37.5% were attributed to congenital heart disease and 12.5% to single-gene disorders (3). Several factors, including those shown below, may contribute to the high prevalence of genetically determined disorders in the region. The high consanguinity rates, which increase the risks of recessively inherited diseases and multi- factorial disorders. The high frequency of haemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency, probably because of the selective advantage of carriers against falciparum malaria. ' Professor of Medical Genetics, College of Medicine, Mustansi- riya University, Baghdad, Iraq. 2 Regional Adviser in Noncommunicable Diseases, WHO Regional Office for the Eastern Mediterranean, P.O. Box 1517, Alexandria-2151 1, Egypt. Requests for reprints should be sent to this author. Reprint No. 5463 - The social trend of continuing to bear children up to menopause, which increases the predisposition to trisomies such as Down syndrome, owing to increased matemal age; also, the incidence of certain autosomal dominant disorders increases with patemal age. - The general lack of public health measures directed at the prevention of genetic diseases and the dearth of genetic services. Consanguinity studies Consanguineous marriages are favourably looked upon in most Muslim countries, and consanguinity rates are high in Eastem Mediterranean countries. Table 1 shows the consanguinity rates and the rates of first-cousin marriages found in various countries in the region. The consanguinity rates range from 16.5% to 55% Table 1: Consanguinity rates and first cousin marriages in some countries of the Eastern Mediterranean Region Total consanguinity % first-cousin Country (ref.) rate (%) marriages Egypt (4) 29 11.4 Iraq (5) 57.9 30 Jordan (6) 50 32 Kuwait (7) 54.3 30.2 Lebanon (8) Christians 16.5 7.9 Muslims 29.6 17.3 Saudi Arabia (2, 9) 55 31.4 Bulletin of the World Health Organization, 1994, 72 (1): 145-154 © World Health Organization 1994 145 H. Hamamy & A. Alwan The rates of first-cousin marriages are closely similar (around 30%) in Iraq, Jordan, Kuwait, and Saudi Arabia. In Lebanon, the rates of consanguinity and of first-cousin marriage are higher among Mus- lims than Christians. Consanguinity, as defined in WHO guidelines, is a marriage between individuals who are second cousins or more closely related.a However, some studies on consanguinity rates include marriages between third cousins. Although this discrepancy affects the total consanguinity rate, it does not markedly alter the average inbreeding coefficient. Uniformity of the definitions used in consanguinity studies is essential for making com- parisons between populations. Calculation of the average inbreeding coefficient or restricting the study to first-cousin marriages are ways of increas- ing the reliability of investigations. It is important, also, to define the population studies in terms of religious, ethnic and socioeconomic criteria, as well as the methods used for ascertainment. Among the offspring of consanguineous mar- riages worldwide, there is an increased postnatal mortality rate and an increased frequency of congen- ital malformation (10, 11). Several studies have been conducted in countries of the region to investigate the risks of consanguinity on reproduction (5, 8, 9, 12-15); however, because of discrepancies in the methodologies used, comparisons between the re- sults are difficult to make. In the Islamic Republic of Iran, a study that analysed the association between consanguinity and congenital defects revealed that the incidence of major congenital malformations was 4% among the newbom of consanguineous parents, compared with only 1.7% among the newborn of non-related parents (16). Moreover, reports from Egypt and Iraq have demonstrated that the consan- guinity rate among parents of mentally handicapped children was higher than that of the general popula- tion (17)." Consanguinity poses the most serious effects when a recessive disorder is present in the family. The chance in a first-cousin marriage of having an affected child is considerably greater than in the case of unrelated parents. Autosomal recessive disorders appear to account for a substantial proportion of physical and mental handicap in the region (18-21).c a Model education aids to assist in haemoglobinopathy controL WHO unpublished document HMG/WF/85.8a, 1985. b Al-Hakeem S, Hamamy H. Genetic studies on institutionalized mentally retarded males with special reference to the fragile X syndrome (Extracted from Al-Hakeem, S. Genetic studies on institutionalized mentally retarded males. MSc thesis, Al-Mustan- siriyah Medical College, Baghdad, 1992). c Zakzouk S et al. The final report: hearing impairment among Saudi infants and children. Epidemiologic and etiological study. King Saud University Project, 1990. Despite the excess postnatal mortality associated with consanguineous marriages, there have been no reports of significant differences in the number of surviving children of marriages between related and non-related individuals. This has been explained by the higher fertility rates of consanguineous couples (22). The practice of marrying relations is unlikely to decline, and therefore genetic diseases will become more prevalent as other causes of mortality and mor- bidity decline (10). Discouraging marriages between cousins is neither feasible nor desirable. However, an altema- tive approach is to focus on families affected by re- cessive conditions by establishing genetic counsel- ling services. Such counselling must be given by ex- perienced professionals and the response of coun- selled families must be evaluated. Limited experience in the region suggests that counselling on the risks of further intermarriages in families with auto- somal recessive conditions is hampered by difficulties related to deeply rooted social customs and beliefs. Furthermore, considerable differences exist in the reaction of families to genetic counselling. Congenital malformation rates Congenital malformations arise at the time of conception or during intrauterine development, and are thus present at birth. The factors that contribute to the etiology of congenital malformations include single-gene disorders, chromosome abnormalities, multifactorial inheritance, and environmental factors. There are considerable ethnic and geographical variations in the incidence, frequency, and distribu- tion of congenital malformations. In developed coun- tries such as the United Kingdom, malformations account for a substantial proportion (26-34%) of perinatal mortality (23). A similar situation is report- ed for the Eastem Mediterranean Region. Recent studies on perinatal mortality have drawn attention to the high contribution of congenital anomalies to peri- natal deaths. A review of perinatal mortality in the Armed Forces Hospital, Riyadh, over the period 1983-87 found that 35.6% of all perinatal deaths were attributed to congenital malformations; the inci- dence of fatal congenital anomalies was 4.7 per 1000 births (24). Another report, from King Khalid Uni- versity Hospital, Riyadh, revealed a perinatal mortal- ity rate for the period 1982-86 of 14.5 per 1000 births, with 23% of mortalities being attributable to congenital anomalies (25). The traditional pattem of consanguineous mar- riages among Arab and Muslim communities may influence the incidence of congenital malformations. Recent reports from Eastem Mediterranean countries provide useful information on the incidence of con- 146 WHO Bulletin OMS. Vol 721994 Hereditary disorders in the Eastern Mediterranean Region genital malformations among live births. In Bengha- zi, Libyan Arab Jamahiriya, a total of 33 332 chil- dren born live in the period 1982-84 were screened for easily identifiable congenital malformations. These were detected in 2.4% of all infants. Musculo- skeletal malformations accounted for over a third of all the anomalies, while neural tube defects and car- diovascular anomalies represented 5% and 12% of the malformations, respectively (26). In Bahrain, the birth frequency of congenital malformations was studied over the period 1978-85. It was found that these malformations increased in frequency from 7.24 per 1000 in 1978 to 18.5 per 1000 in 1985. Despite this considerable rise, the fre- quency remained within the worldwide range. Here again, anomalies of the musculoskeletal system had the highest frequency, at an average of 2.8 per 1000 (27). Studies specifically focusing on the birth inci- dence of neural tube defects report various rates. In Saudi Arabia, for example, a study of 74 923 births found an incidence of 0.82 per 1000 births, while a previous study had reported an incidence of 1.6 per 1000 (28, 29). In Bahrain, Libyan Arab Jamahiriya, and Tunisia the incidences per 1000 were 1.5, 1.3, and 2.6, respectively (26-30). Throughout the world, the incidence of neural tube defects is decreasing steadily and significantly, and this trend may be valid also for some countries in the Eastern Mediter- ranean Region (28). Further epidemiological studies to evaluate the incidence of congenital malforma- tions in the region are needed; special emphasis also needs to be placed on studies to verify the etiological factors involved. Chromosomal abnormalities Chromosomal aberrations are among the best- defined causes of congenital disease and mental handicap. At birth about 5 per 1000 liveborn children bear a chromosomal abnormality. The magnitude of this problem is difficult to define in the Eastern Medi- terranean Region, because of the lack of technical resources needed to carry out such studies. In one study from the Libyan Arab Jamahiriya the incidence of all chromosomal aberrations at birth was deter- mined to be 2.72 per 1000. This is lower than the global incidence probably because of methodologi- cal differences (26). Down syndrome is one of the commonest chro- mosomal anomalies and its contribution to the etiol- ogy of mental retardation is considerable (almost 30% of cases have been attributed to Down syn- drome (21)).d The average global incidence of Down syndrome is 1.4 per 1000 of livebirths, with devia- d See footnote b, p. 146. tions from this level being proportional to maternal age. Among live births in the region, the following incidences of Down syndrome have been reported: 1.7 per 1000 in the Libyan Arab Jamahiriya (26); 1.14 per 1000 in Bahrain (27); and 1.8 per 1000 in Egypt (31). The factors that predispose to the non-disjunc- tion that results in trisomy have been poorly identi- fied, apart from the well-known influence of increased maternal age. Extrinsic factors such as bio- logical, physical, or chemical mutagens have been implicated as etiological factors; the contribution of genetic factors and the effect of consanguinity have, however, not been clearly defined (22, 32, 33). The contribution of chromosome aberrations to the etiology of early spontaneous abortion is well documented. Up to 50% of abortus specimens reveal chromosome aberrations, with the highest frequency being found among early pregnancy losses (34, 35). The high incidence of chromosomal anomalies among abortus material compared with that among livebirths (0.5%) confirms the power of spontaneous abortion as a tool for early elimination of defective zygotes. Data are limited on the contribution of chromo- some aberrations in spontaneous abortion in the region; however, available reports provide some use- ful information. A study from Saudi Arabia of 78 abortuses of 12-24 weeks' gestation reported a chro- mosome aberration rate of 8% (36). This compara- tively low rate could have arisen because the sam- ples were taken from abortuses after the first trimester. The variation in the contribution of chromosome aberrations to the etiology of early spontaneous abor- tion may be influenced by the possible contribution of other poorly understood genetic factors. It is note- worthy that abortuses may represent lethal equiva- lents of single-gene disorders or multifactorial mal- formations, both of which could be strongly affected by inbreeding levels, which are high in the region. A recent study suggests a predisposition to spontaneous abortion in families where recurrent spontaneous abortion occurs (37). Couples who experience recurrent fetal wastage may manifest a balanced chromosomal abnormality. Several studies, worldwide, have revealed that, on average, in 5-15% of such couples one partner is a carrier of a chromosome abnormality (38). This is of paramount importance in the context of genetic counselling and for estimating prognostic possibil- ities. Cytogenetic studies of couples with repeated spontaneous abortion in Qatar and Iraq have revealed a major chromosomal anomaly in one of the parents for 5.3% and 8% of the families studied, respectively (39, 40). WHO Bulletin OMS. Vol 721994 147 H. Hamamy & A. Alwan Monogenic diseases The haemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency are the common- est single-gene disorders encountered in the region and represent a major health problem; available data indicate that they are commoner here than in many other parts of the world. The chronic ill health and complications of these conditions pose considerable burdens on health services. Studies on the frequency of these disorders in countries of the Eastern Mediterranean Region do not have a uniform geographical distribution. In Saudi Arabia, for example, a considerable number of studies have been undertaken in almost all the prov- inces. The findings provide useful information on the epidemiology of blood genetic disorders and indicate that there is a wide variability in different areas of the country. Contrasting with this situation are coun- tries where these disorders are commonly encoun- tered in clinical practice but for which no prevalence data are available. Understanding about the genetic blood disorders in the region is complicated by the heterogeneity within the thalassaemia group and by the unknown interactions that occur between the different types of haemoglobinopathies and with G6PD deficiency in the same individual. ax- and 3-Thalassaemias may be caused by differ- ent mutations; information about the DNA defects in a given population is valuable and helps to predict phenotypes and plan preventive measures. Molecular studies, which have been initiated in a small number of countries, need to be developed further. The main obstacle is the considerable technical requirements needed for such programmes. Sickle cell disease Several studies in Saudi Arabia have reported inci- dences of 2-27% for the carrier state for sickle cell disease and an incidence of around 1.4% for sickle cell anaemia. The highest rates are in the eastern region and the lowest in the central region of the country (41-45). In Bahrain, sickle cell trait has been identified in 11-18% of neonates (46, 47), and sickle cell disease was reported to have an incidence of 2.1% among screened newborns. Lower levels have been reported from the Liby- an Arab Jamahiriya. In the south of the country a prevalence of 4.4% and 1.2% for sickle cell trait and sickle cell anaemia, respectively, has been found; there is considerable geographical variation in the level of abnormal haemoglobin, with the prevalence of sickle cell anaemia being only 0.005% in the east of the country (48). Among Omani subjects, 6.1% were shown to be heterozygotes for HbA and HbS, with an estimated 3.7 homozygotes per 1000 live births (49). ,B-Thalassaemia As discussed above, the distribution of P-thalassaemia in Saudi Arabia varies according to the region. The carrier frequency lies in the range 1-15% (43, 44). In Libyan Arab Jamahiriya, the highest carrier state for ,-thalassaemia has been found in the eastem region (11.2%), followed by the southem (3.2%), while the lowest is in the north-east (0.92%) (48, 50). In Pakistan, the prevalence of the carrier state has been reported to be 1.5% in Karachi and 1.6% in Rawal- pindi (51, 52). The frequency of heterozygotes in Cyprus is 15-17% (53). a-Thalassaemia Although it was previously believed that ax-thalas- saemia was uncommon in the region, recent reports suggest that it is a problem of significant dimensions. Carrier state levels in the range 2-40% have been reported in Saudi Arabia and in Bahrain levels of 24.2% among neonates have been found (43, 44, 46). Glucose-6-phosphate dehydrogenase deficiency A total of 7.5% of the world's population carry one or two genes for G6PD, the proportion ranging from a maximum of 35% in parts of Africa to 0.1% in Japan and parts of Europe. About 2.9% of the global population is genetically G6PD deficient (54). Although the condition is X-linked recessive, owing to the high gene frequency and consanguinity in the Eastern Mediterranean Region, homozygote females represent 10% of those who are genetically G6PD deficient. Also, 10% of heterozygote females are G6PD deficient because of unequal activation of the X-chromosome. Several epidemiological surveys to determine the frequency of G6PD deficiency in different coun- tries of the region have been conducted. The results confirm that the problem is a common genetic dis- order. Not all countries in the region have been covered to the same extent in these surveys; in some countries, several extensive, accurate studies were performed, while in others only limited non- standardized methodologies were used. Screening for G6PD deficiency is best per- formed for males only and for a certain age group. A screening test that gives the most accurate results should be used. Table 2 shows the frequency of G6PD deficien- cy in different countries of the region. WHO Bulletin OMS. Vol 72 1994148 Hereditary disorders In the Eastern Mediterranean Region Table 2: Prevalence of glucose-6-phosphate dehydro- genase (G6PD) deficiency In some countries in the Eastern Mediterranean Region Country (ref.) % G6PD deficient (sex screened) Bahrain (46) 20.9 (both sexes) Egypt (55) 4 (both sexes) Iran (Islamic Republic of) (56) 17.88-22.8 (males) Iraq (57-59) 9-12 (males) 13 (both sexes) Jordan (60) 10 (males) Libyan Arab Jamahiriya (61) 2.5 (males) Oman (49) 27.3 (males) Saudi Arabia (42, 44, 62-64) 4.5-43 (males) Cystic fibrosis Cystic fibrosis is the commonest fatal genetic disease among Caucasians, for whom the incidence reaches 1:2000. The incidence is much lower among Blacks (1:17 000) and is very rare among American Orien- tals (1:93 000). The incidence levels of cystic fibrosis have recently been reported for some countries in the Eastern Mediterranean Region. The data suggest that the disease might be as common as in Europe. In Saudi Arabia, cystic fibrosis has been reported in 1:4243 children under 14 years of age (65), while in Jordan the incidence among newborns is 1:2560 (66). Cases have been reported also from the Islamic Republic of Iran, Iraq, Kuwait, Lebanon, Pakistan, and among Palestinians. Congenital hypothyroidism Screening for congenital hypothyroidism is now car- ried out in many programmes. The condition has been identified in approximately 1:3600 to 1:5000 newborns (1). Although only a few of the etiologies for congenital hypothyroidism are Mendelian, screening for this condition is commonly combined with screening of newborns for principally genetic disorders. The aim of the screening is to detect af- fected newborns as early as possible to permit timely management to minimize severe clinical sequelae. Screening for congenital hypothyroidism has been performed in some countries of the region and inci- dences among liveborn infants of 1:2666 and 1:1433 have been reported from Saudi Arabia and the Islamic Republic of Iran, respectively (67, 68). Other monogenic conditions Since the occurrence of genetic diseases varies wide- ly, both geographically and ethnically, it would be interesting to study their epidemiological pattern in the region, which is characterized by distinct ethnic groups and high consanguinity rates. Reports from countries in the region have point- ed to higher frequencies of various autosomal reces- sive conditions, e.g., Laurence-Biedl syndrome and multiple pterygium syndrome (prevalence, 1 per 36 000 for each in Kuwait (69)), while in Oman a prevalence of 1.2 per 10000 live births has been reported for spinal muscular atrophies (70). Screening programmes for monogenic disorders Genetic diseases cause considerable human suffering and place an increasing burden on health care sys- tems. Prevention programmes based on local circum- stances should be formulated through comprehensive national plans. In some countries in the region, screening programmes for congenital diseases of newborn infants have been in effect for several decades. For example, newborn screening pro- grammes have been initiated in Saudi Arabia and Bahrain (42, 46, 68) and have provided valuable information on the incidence of haemoglobinopa- thies, G6PD deficiency and congenital hypothy- roidism. The aims of such programmes include the establishment of incidences for various genetic dis- eases and early identification of those affected in order to initiate prompt management and prevent the birth of new cases in high-risk families. In the Aramco screening programme (42), no case of phenylketonuria was detected among 70 000 newborns screened. In Caucasians the average inci- dence of phenylketonuria is 1 per 10000, and in Turkey, where the consanguinity rate is 21%, the frequency of phenylketonuria was found to be 1 per 4370 newborns (71). Since screening during the neonatal period can be performed for several conditions, it is critical to decide, in the light of available resources and epi- demiological trends, which diseases should be screened for and what are the priorities for countries of the region. Multifactorial disorders For many common disorders that have a familial clustering, no single gene can be held responsible; rather they are determined by many genes interacting with environmental factors. Such genetic-environ- mental interaction is believed to operate in the etiology and pathogenesis of hypertension, diabetes, and schizophrenia. The prevalences of hypertension, diabetes, and coronary heart disease are growing significantly in WHO Bulletin OMS. Vol 72 1994 149 H. Hamamy & A. Alwan the Eastern Mediterranean Region. Cardiovascular diseases are now the leading cause of death in many countries of the region and available epidemiological data suggest that many of their populations have a high susceptibility to hypertension and diabetes. Prevention and control programmes for these disorders should be based on the modification of lifestyle characteristics to prevent environmental risk factors from developing. While such programmes can be directed at the community as a whole, partic- ularly in high prevalence areas, special emphasis should also be given to those at high risk. Identifica- tion of persons with a genetic predisposition to these disorders is therefore an important component of prevention and control programmes. Genetic factors in infertility A wide range of mutant genes and chromosomal abnormalities can disturb gamete formation and function in men, resulting in infertility. A significant proportion of men who are attending infertility clinics may have single-gene disorders; the higher consanguinity rates among the parents of undiag- nosed cases of azoospermia in Baghdad (72) may in- dicate the involvement of autosomal recessive genes. Various chromosomal disorders contribute to male infertility. Klinefelter syndrome is the most prominent of these, and accounted for 22% of azo- ospermic males referred to one cytogenetic labora- tory in the region (72). Female infertility may also result from chromo- somal abnormalities or single-gene disorders. For example, Turner syndrome was diagnosed in 8.5% and autosomal recessive disorders in 8% of females with primary amenorrhoea who were referred for chromosome analysis in Iraq (73, 74). Also, in a study of intersexual disorders in Egypt, recessive inheritance was the predominant etiological factor (75). Cytogenetic studies on patients with puberty problems in Tunisia revealed that 26% had chromo- somal abnormalities and that 8% of infertile couples had chromosomal anomalies (76). Cytogenetic studies of infertility should there- fore be carried out in the region, with subsequent, appropriate genetic counselling. Conclusions * Considerable achievements have been made over the last two decades in the control of communicable diseases in the Eastern Mediterranean Region. The incidences of infections and of nutritional disorders are declining in most Member States. Concurrently, these has been a mounting awareness of the increas- ing importance of hereditary disorders. Certain genetically determined diseases, e.g., the haemoglo- binopathies and enzymopathies, are extremely com- mon in the region and the need to initiate public health measures for their control is being increasing- ly recognized. Political will and national commit- ment at the highest level are the basic requirements for the success of prevention programmes. * The high consanguinity rates among the popula- tions of countries in the region constitute the most important risk factor, leading to increased prevalence of autosomal recessive conditions and possibly also multifactorial disorders. Studies of the prevalence of consanguinity in different countries are indicated. Such studies could provide essential information for evaluating the burden of genetic diseases and moni- toring future trends in the region. The impact of consanguinity on reproductive health could be investigated by studying patients with reproductive dysfunction, e.g., infertile individ- uals, couples with repeated fetal wastage, children with mental retardation, and infants with congenital malformations. Among the unresolved questions are the effect of consanguinity on the rate of spontane- ous abortions influenced by the sharing of common antigens by the couple at the histocompatibility locus; and the effect of consanguinity on fertility. Consanguinity studies can provide basic data on the prevalence of autosomal recessive conditions in populations. Comparison of the relative incidence of first-cousin marriages among the parents of those affected and that of the general population provides a simple method for assessing the frequency of the abnormal gene; the higher the consanguinity rate among the parents of those affected, the rarer is the condition among the general population. Standardized methodologies and guidelines are needed to validate future comparisons between the various geographical, ethnic, and socioeconomic groups studied. * Despite the scarcity of data, congenital malforma- tions in countries of the Eastern Mediterranean Region appear to be occurring at rates similar to those in developed countries, and account for a con- siderable proportion of perinatal mortality and child morbidity. More data are needed on the rates and types of congenital malformations in various countries of the region. Also, priority should be given to research on the major underlying etiologies and the contribution of potential environmental teratogens versus genetic factors. In the meantime, prevention programmes can be established, whenever appropriate, to focus pri- marily on health education, genetic counselling, and avoidance of known teratogens. WHO Bulletin OMS. Vol 72 1994so0 Hereditary disorders in the Eastern Mediterranean Region * There have been no cytogenetic screening pro- grammes in the region to evaluate the incidence of chromosomal anomalies at birth. However, the pro- portion of mothers over 35 years of age is reportedly high, a factor which may predispose to increased rates of trisomies, particularly Down syndrome. Screening programmes for chromosomal anomalies are justified where resources are available. These can provide valuable information to assess the magnitude of the problem and to define future trends, taking into consideration potential environmental influences in the region. * The haemoglobinopathies, the commonest mono- genic disorder in the region, can be prevented by programmes involving health education, genetic counselling, and newborn and heterozygote diagno- sis. Newborn screening for sickle cell anaemia has the advantage of early diagnosis of those affected, which is important for better management and for early genetic counselling of families at high risk. The importance of such counselling is more pronounced in countries where families tend to have large sib- ships. A heterozygote screening programme for p- thalassaemia has been conducted in Cyprus. The aim was to diagnose carriers and to offer them genetic counselling and fetal diagnosis if indicated. The pro- gramme was very successful in reducing the birth rate of thalassaemia major to about 6% of that expected over a period of 15 years. Such pro- grammes depend on advanced laboratory and obstet- ric technologies, with screening integrated into primary health care. The feasibility and success of such services in countries with large populations in the region should be investigated. The complications of G6PD deficiency can be prevented by establishing screening programmes, combined with health education. * Genetic counselling is the best practical method for minimizing the number of children born with genetic disorders and congenital malformations. This aspect of preventive medicine is just beginning to develop in some countries of the region where genet- ic counselling clinics have begun to function in teaching hospitals; these clinics need as much sup- port and guidance as they can get. Expansion of such services to cover all countries of the region is urgent- ly needed. Prevention of genetic diseases through counsel- ling should be established as a basic component of the medical curriculum to enable physicians in pri- mary and higher levels of health care to deal with simple, commonly encountered genetic problems. There is a need to promote health system research aimed at identifying appropriate approaches and to determine the impact of genetic counselling at the primary health care level. Research should also be carried out to assess the attitudes of families towards what they learn in genetic counselling ses- sions and their ultimate reaction to the advice pro- vided. * Fetal diagnosis of genetic diseases has become an active preventive measure in developed countries. Various methods, such as chorion villus biopsy, amniocentesis, and ultrasound examination, are cur- rently used to diagnose chromosome anomalies, single-gene disorders, and birth defects. Cyprus is one country in the region where ante- natal diagnosis is practised within the national thalassaemia prevention programme. The ethical, religious and social acceptability of this approach in other countries of the region have, however, not ad- equately been explored. An antenatal diagnosis ser- vice can only operate within the framework of locally adopted general guidelines on therapeutic abortion. * Setting up computerized registers of genetically determined diseases is justified in some countries of the region. Such registers could provide valuable information about families at high risk of recurrence. The main function of the register would be to offer prospective genetic counselling to members of the population at high risk of having abnormal offspring. The systematic long-term follow-up of such registers would also facilitate monitoring genetic services as well as future epidemiological trends. Although birth defects monitoring is a difficult task in large populations with poor record systems, in some countries of the region newborn screening for congenital malformations has provided valuable epidemiological information. * The highly sophisticated technology linked nowa- days to medical genetics should not be seen as a pre- requisite to the provision of community genetic ser- vices or the initiation of genetic research programmes. Preventive strategies using simple techniques, public education, and genetic counselling can also provide valuable results. * Even in countries with minimal resources, at least one national genetic centre should be established to provide medical services, train health professionals in the various aspects of medical genetics, and carry out research. * Up-to-date diagnostic techniques should be intro- duced whenever national resources permit. These should include DNA technology and the various cytogenetic procedures for diagnosing single-gene and chromosomal disorders. * Promotion of active collaboration, coordination and exchange of experiences between the Member WHO Bulletin OMS. Vol 72 1994 151 H. Hamamy & A. Alwan States and regional institutions and professionals concerned should be given priority in the regional Programme for Prevention of Hereditary Disorders. Resume Troubles hereditaires dans la R6gion de la M6diterran6e orientale Les maladies h6reditaires et les malformations cong6nitales touchent 2 a 5% de 1'ensemble des naissances vivantes. Elles motivent jusqu'a 30% des hospitalisations en service pediatrique et sont responsables de la moitie environ des deces d'enfants dans les pays developpes. Contraire- ment a une id6e reque, il semble que les troubles gen6tiques soient tout aussi importants dans les pays de la R6gion de la Mediterranee orientale. D'apres une enquete r6alisee dans un h6pital d'Arabie saoudite de 1985 a 1989, pres de 16% des enfants hospitalis6s presentaient des anoma- lies cong6nitales et des troubles d'origine g6n6- tique. Parmi les d6ces d'enfants observ6s en 1985 dans un hopital du Koweft, 37,5% ont ete attribu6s a une cardiopathie cong6nitale et 12,5% a des troubles monogeniques. Plusieurs facteurs peuvent contribuer a la forte prevalence des troubles d'origine g6n6tique dans la R6gion, notamment: un taux 6leve de consanguinit6, qui augmente le risque de troubles r6cessifs et de troubles multifactoriels; la fr6quen- ce elevee des hemoglobinopathies et du deficit en glucose-6-phosphate deshydrog6nase, probable- ment due a l'avantage s6lectif des porteurs vis-a- vis du paludisme a falciparum; la tendance a avoir des enfants jusqu'a la menopause, qui augmente la pr6disposition aux trisomies comme le syndro- me de Down, en raison de l'age maternel 61ev6, tandis que l'incidence de certaines maladies a transmission autosomique dominante augmente avec l'ge paternel; et I'absence generale de mesures de sant6 publique ax6es sur la pr6ven- tion des maladies gen6tiques, tout comme l'absence de consultations g6n6tiques dans la Region. Ces vingt dernieres ann6es, des progres consid6rables ont 6t6 r6alis6s dans la lutte contre les maladies transmissibles dans la R6gion de la Mediterran6e orientale. L'incidence des infections et des maladies nutritionnelles diminue dans la plupart des Etats Membres de la Region; parall&- lement, I'importance des troubles her6ditaires est de plus en plus reconnue. Certaines maladies d'origine gen6tique comme les h6moglobinopa- thies et les enzymopathies sont tres repandues dans la R6gion, et la necessite de mettre en place des mesures de sant6 publique destin6es a les combattre est de plus en plus souvent pergue. La prevention des maladies genetiques par le conseil genetique devra etre introduite dans les programmes d'etudes m6dicales de fagon A per- mettre aux medecins, quel que soit le niveau de soins de sant6 dont ils relevent, de prendre en charge des problemes g6netiques simples mais frequents. L'acceptabilite ethique, religieuse et sociale du conseil genetique n'a pas 6t6 assez 6tudi6e dans 1'ensemble des pays de la R6gion. Les services de conseil genetique ne peuvent fonctionner que dans le cadre de directives adop- tees localement. La promotion d'une collaboration active, d'une coordination et d'un echange d'exp6riences entre les Etats Membres, les institutions r6gionales et professionnels de la sante concern6s devra constituer l'une des taches prioritaires du pro- gramme r6gional de pr6vention des troubles h6r6- ditaires. References 1. Emery AEH, Rimoin DL. Principles and practice of medical genetics, 2nd ed. Edinburgh, Churchill Livingstone, 1990. 2. Bahakim H et al. Pediatric inpatients at the King Khalid University Hospital, Riyadh, Saudi Arabia, 1985-1989. Annals of Saudi medicine, 1993, 13(1): 8-13. 3. Al-Najdi KN et al. Pattern of morbidity among hos- pitalised children - a one-year retrospective study. Journal of the Kuwait Medical Association, 1989, 23: 158-162. 4. Hafez M et al. Consanguineous matings in the Egyptian population. Journal of medical genetics, 1983, 20: 58-60. 5. Hamamy H et al. Consanguineous matings in the Iraqi urban population and the effect on pregnancy outcome and infant mortality. Iraqi medical journal, 1986, 34: 75-80. 6. Khoury SA, Massad D. Consanguineous marriage in Jordan. American journal of medical genetics, 1992, 43: 769-775. 7. Al-Awadi SA et al. Consanguinity among the Kuwaiti population, Clinical genetics, 1985, 27: 243-246. 8. Khlat M. Consanguineous marriage and reproduc- tion in Beirut, Lebanon. American journal of clinical genetics, 1988, 43: 188-196. 9. Wong S, Anokute C. The effect of consanguinity on pregnancy outcome in Saudi Arabia. Journal of the Royal Society of Health, 1990, 4: 146-147. 10. Bittles A et al. Reproductive behaviour and health in consanguineous marriages. Science, 1991, 252: 798-794. 11. Khlat M, Khoury M. Inbreeding and diseases. De- mographic, genetic and epidemiologic perspectives. 152 WHO Bulletin OMS. Vol 72 1994 Hereditary disorders in the Eastern Mediterranean Region Epidemiologic reviews, 1991, 13: 28-41. 12. Hamamy H, Al Hakkak Z. Consanguinity and repro- ductive health in Iraq. Human heredity, 1989, 39: 271-275. 13. Al Awadi SA et al. The effect of consanguineous marriage on reproductive wastage. Clinical genetics, 1986, 29: 384-388. 14. Cook R, Hansllp A. Mortality among offspring of consanguineous marriage in a rural area of East Jordan. Journal of tropical pediatrics and environ- mental child health, 1966, 11: 95-99. 15. Saha N et al. Inbreeding effects on reproductive outcome in a Sudanese population. Human heredity, 1990, 40: 208-212. 16. Naderi S. Congenital abnormalities in newborns of consanguineous and non-consanguineous parents. Obstetrics and gynecology, 1979, 53: 195-199. 17. Hafez M et al. Genetic counselling for the preven- tion of recurrence of mental retardation. Bulletin of the High Institute of Public Health, Alexandria, 1983, 13(2): 163-183. 18. Hamamy H. Genetic factors in congenital malforma- tions. In: Proceedings of the Fifth Scientific Confer- ence of the Scientific Research Council, Baghdad. Baghdad, Ministry of Higher Education, 1989. 19. Kabarity A et al. Autosomal recessive, uncomplica- ted, profound childhood deafness in an Arabic fami- ly with high consanguinity. Human genetics, 1981, 57: 441-446. 20. Ben Arab S et al. An epidemiological and genetic study of congenital profound deafness in Tunisia (governorate of Nabeul). Journal of medical genetics, 1990, 27: 29-33. 21. Hafez M et al. Etiologic factors in mental subnor- mality among Egyptian children. Gazette of the Egyptian Paediatric Association, 1984, 32: 65-72. 22. Consanguinity and health. Lancet, 1991, 338: 85-86. 23. Young I, Clarke M. Lethal malformations and peri- natal mortality: a 10-year review with comparison of ethnic differences. British medical journal, 1987, 295: 89-91. 24. Agwiser A. Perinatal mortality at the Armed Forces Hospital Riyadh, Saudi Arabia: five-year review of 22,203 births. Annals of Saudi medicine, 1990, 10: 268-275. 25. Haque K, Bashi 0. Perinatal mortality at King Khal- id University Hospital Riyadh. Annals of Saudi medi- cine, 1988, 8: 190-193. 26. Mir N et al. Easily identifiable congenital malforma- tions in children; survey of incidence and patterns in 32,332 liveborn neonates. Annals of Saudi medi- cine, 1992, 12: 366-371. 27. Al-Arrayat S. Congenital anomalies in Bahrain. Bahrain medical bulletin, 1987, 9: 70-73. 28. El-Hag El-Awad M, Sivasankaran S. Neural tube defects in Southwest region of Saudi Arabia. Annals of Saudi medicine, 1992, 12: 449-452. 29. Thalij A et al. Incidence of neural tube defects in the Eastern Province of Saudi Arabia. Journal of the Kuwait Medical Association, 1986, 20: 99-104. 30. Marrakchi Z et al. Epidemiologic aspect of central neurologic congenital malformations. Tunisie m6di- cale, 1991, B9: 625-632. 31. Hafez M et al. Demographic trends of Down's syn- drome in Egypt. Journal of the Egyptian Medical Association, 1983, 66: 495-507. 32. Hamamy H et al. Consanguinity and the genetic control of Down's syndrome. Clinical genetics, 1990, 37: 24-29. 33. Nagulb K et al. Effect of parental age, birth order and consanguinity on non-disjunction in the popula- tion of Kuwait. Journal of the Kuwait Medical Asso- ciation, 1989, 23: 37-43. 34. Edwards RF. Causes of early embryonic loss in human pregnancy. Human reproduction, 1988, 1: 185. 35. Vogel F, Motulsky AG. Human genetics: problems and approaches, 2nd ed. Berlin, Springer-Verlag, 1986. 36. Meshari A et al. Cytogenetic investigation on fetus- es from spontaneous abortions. Saudi medical jour- nal, 1990, 11: 380-384. 37. Christiansen 0 et al. Idiopathic recurrent spontane- ous abortion. Evidence of a familial predisposition. Acta obstetricia et gynecologica Scandinavica, 1990, 69: 597-601. 38. Plouffe L Jr et al. Reproductive outcomes of chro- mosomal translocation carriers. In: Abstracts of the 46th Annual Meeting of the American Fertility Soci- ety, Washington, DC., 13-18 October 1990. (Fertility and sterility, 1990, 54: 524). 39. Al-Ali K, Hozier J. Cytogenetic investigation of cou- ples with multiple spontaneous abortions in Qatari population. In: Proceedings of the Eighth Interna- tional Congress of Human Genetics, 6-11 October 1991, Washington, DC. (American journal of human genetics, (suppl.) 1991, 49(4)). 40. Hamamy H, Al Taha S. Chromosomes studies in 100 couples with repeated fetal wastage. Jordan medical journal (in press). 41. Niazi G, Rowland H. Haemoglobinopathies - a review. Saudi medical journal, 1989, 10: 340-352. 42. Abu-Osba Y et al. Comprehensive newborn screen- ing program: Aramco experience, the national need and recommendations. Annals of Saudi medicine, 1992, 12: 235-240. 43. El-Hazmi M. Incidence and frequency of haemoglo- binopathies and thalassemia in the north-west sec- tor of Arabia. Saudi medical journal, 1985, 6: 149- 162. 44. El-Hazmi M. The red cell genetics and environ- mental interactions. A Tehamat - Aseer profile. Saudi medical journal, 1985, 6: 101-112. 45. El-Hazmi M, Warsy A. The frequency of glucose-6- phosphate dehydrogenase phenotype and sickle cell gene in Al-Qassim. Annals of Saudi medicine, 1992, 12: 463-467. 46. Mohammed A et al. Haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in hospital births in Bahrain. Annals of Saudi medicine, 1992, 12: 536-539. 47. Nadkarni K et al. Incidence of genetic disorders of hemoglobins in the hospital population of Bahrain. Bahrain medical bulletin, 1991, 13: 19-24. 48. Sheriff S et al. A profile of abnormal haemoglobins in eastern and southern Libya. Saudi medical jour- nal, 1989, 10: 138-140. 49. White JM et al. Frequency and clinical significance of erythrocyte genetic abnormalities in Omanis. WHO Bulletin OMS. Vol 721994 153 H. Hamamy & A. Alwan Journal of medical genetics, 1993, 30: 396-400. 50. Mangoush M et al. Prevalence of thalassemia in north-eastern Libya. Saudi medical journal, 1990, 11: 280-282. 51. Saleem M et al. Distribution pattern of haemoglo- binopathies in northern areas of Pakistan. Journal of the Pakistan Medical Association, 1985, 35: 106-109. 52. Hameed M. Hereditary persistence of fetal hemoglo- bin and thalassemia trait incidence in our population (a study of 300 adults and subjects). Rawal medical journal, 1984, 13(3, 4): 1-9. 53. Angastiniotis M et al. The Cyprus Thalassemia Control Programme. Birth defects (original article series), 1988, 23: 417-432. 54. WHO Working Group. Glucose-6-phosphate dehy- drogenase deficiency. Bulletin of the World Health Organization, 1989, 67: 601-611. 55. Mohareb S et al. Some aspects of G6PD deficiency anemia in the north-east delta. Gazette of the Egyp- tian Paediatric Association, 1985, 33: 163-170. 56. Edrissian G et al. Malarial antibodies and glucose- 6-phosphate dehydrogenase deficiency. Iranian jour- nal of public health, 1983, 12: 9-25. 57. Amin Zaki L, Eldin SA. Glucose-6-phosphate dehy- drogenase deficiency among ethnic groups in Iraq. Bulletin of the World Health Organization, 1972, 47: 1-5. 58. Hamamy H, Saeed K. Glucose-6-phosphate dehy- drogenase deficiency in Iraq. Human genetics, 1981, 58: 434-435. 59. Al-Naama L et al. Human erythrocytes glucose-6- phosphate dehydrogenase and 6-phosphagluconate in Basrah area. Journal of the Faculty of Medicine, Baghdad, 1984, 26: 101-109. 60. Madanat F et al. Glucose-6-phosphate dehydro- genase deficiency in male newborns. Jordan medi- cal journal, 1986, 21(2): 205-212. 61. El-Fakhri M et al. Glucose-6-phosphate dehydro- genase deficiency in Libya: an appraisal of gene frequency in Arabic regions of Africa and West Asia. Garyounis medical journal, 1985, 8: 143-146. 62. El-Hazmi M, Warsy A. Glucose-6-phosphate dehy- drogenase deficiency: genetic, pathophysiologic and therapeutic aspects. Annals of Saudi medicine, 1985, 4: 213-223. 63. White J et al. G6PD deficiency in Saudi Arabia: fre- quency, activity and clinical significance. Saudi med- ical journal, 1990, 11: 208-214. 64. Ranasinghe W et al. G6PD deficiency in newborn infants of Eastern Saudi Arabia. Annals of Saudi medicine, 1988, 8: 356-358. 65. Mathew PM et al. Cystic fibrosis presenting with recurrent vomiting and metabolic alkalosis. Euro- pean journal of pediatrics, 1991, 150: 264-266. 66. Nazer H. Early diagnosis of cystic fibrosis in Jorda- nian children. Journal of tropical pediatrics, 1992, 38: 113-115. 67. Al-Nuaim A et al. Neonatal screening for congenital hypothyroidism: incidence, imaging, feasibility and difficulties of a nationwide programme. Annals of Saudi medicine, 1992, 12: 129-134. 68. Karamizadeh Z, Amrihakimi G. Incidence of con- genital hypothyroidism in Fars Province, Iran. Ira- nian journal of medical sciences, 1992, 17: 78-80. 69. Teebi A. Mendelizing inborn errors of morphogene- sis among the Arabs: an overview from Kuwait. Journal of the Kuwait Medical Association, 1990, 24: 122-1 24. 70. Rubello Pento M, Buhl L. Prevalence of spinal muscular atrophy in Oman: a six-month study. Emi- rates medical journal, 1992, 10: 131-136. 71. Ozguc M et al. Mutation analysis in Turkish phenyl- ketonuria patients. Journal of medical genetics, 1993, 30: 129-131. 72. Hamamy H, Al-Taha S. Cytogenetic investigations on a referred population of azoospermic males. Journal of the Faculty of Medicine, Baghdad, 1989, 31: 311-315. 73. Hamamy H, Al-Taha S. Cytogenetic investigations among 201 females with primary amenorrhea. Jour- nal of the Faculty of Medicine, Baghdad, 1989, 31: 317-321. 74. Hamamy H. Chromosome studies and genetic counselling in Baghdad: one year experience. Saudi medical journal, 1984, 5: 46-52. 75. Abdel Salam M et al. Familial intersexual disorders. Gazette of the Egyptian Paediatric Association, 1983, 31(3, 4): 7-17. 76. Chaabouri H et al. Cytogenetic study on 500 selected patients with suspected chromosomal aber- rations. Tunisie m6dicale, 1992, 70: 39-43. 154 WHO Bulletin OMS. Vol 72 1994