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2. Multifactorial diseases
2. MULTIFACTORIAL DISEASES 2.1. General aspects (11) Naturally occurring genetic diseases contribute substantially to human morbidity and mortality. These are broadly classi®ed into mendelian, chromosomal (due to numerical or structural abnormalities of chromosomes), and multifactorial diseases. The current estimates of incidence in live births of mendelian and chromosomal diseases is of the order of 2.8% (i.e. mendelian diseases, 2.4% and chromosomal diseases, 0.4%) (Sankaranarayanan, 1998; UNSCEAR, 1977). In contrast, multifactorial diseases have a far higher population prevalence (well over 70%) indicating their importance both in terms of the numbers of aected individuals and the impact on health-care facilities (Czeizel and Sankaranarayanan, 1984; Czeizel et al., 1988a). (12) As the name implies, these diseases are interpreted to result from a large number of causes, both genetic and environmental; each of these causes has a small eect but when acting together produce the disease in question. The common congenital abnormalities (e.g. neural tube defects, cardiovascular malformations, cleft lipcleft palate) and many common conditions of adult onset (e.g. coronary heart disease, diabetes mellitus, essential hypertension, epilepsy, schizophrenia, aective psychoses) are examples of multifactorial diseases. These are aetiologically heterogeneous. In terms of transmission characteristics, the majority do not ®t mendelian expectations, but occur at higher frequencies among the relatives of aected individuals than in the general population. 2.2. Congenital abnormalities (13) Congenital abnormalities (CAs) are gross or microscopic structural defects present at birth whether detected at that time or not. The adjective `congenital' signi®es only their presence at birth and has no aetiological connotation. The CAs are the end-results of dysmorphogenesis and can occur as isolated or multiple entities. Isolated CAs are those structural defects each of which can be traced back to one localised error in morphogenesis; multiple CAs are due to two or more dierent morphogenetic errors occurring during development of the same individual (see Opitz, 1982; Czeizel and Tusnady, 1984 and Czeizel et al., 1988 for detailed discussions). Further, the earlier the disturbance in morphogenesis, the more severe is the defect. It should be emphasised here that all CAs, including their least severe forms, are all-or-none traits, i.e. they are not metric traits and at their least severe end do not shade into normality (Opitz, 1982). 2.2.1. Overall prevalences (14) A vast body of data on the incidences of CAs in dierent parts of the world has been published (e.g. Stevenson et al., 1966; Myrianthopoulos and Chung, 1974; Trimble and Doughty, 1974; Carter, 1976; Leck, 1976; 1977; Kalter and Warkany, 1983; Czeizel and Tusnady, 1984; Czeizel and Sankaranarayanan, 1984; Czeizel et 17
ICRP Publication 83
al., 1988b; Brent, 1986; Baird et al., 1988; reviewed in Sankaranarayanan et al., 1994). The estimates in these and other studies not referred to above, vary widely from about 1% in live births to a high of about 8.5% in total births (i.e. still+live births) depending on, among others, de®nition, classi®cation, and diagnostic criteria, entities included, method of ascertainment, duration of follow-up of live-born children, sample sizes, etc. (15) Table 2.1 compares the birth frequency estimates of CAs in Hungary (Czeizel and Sankaranarayanan, 1984) with those in the Canadian province of British Columbia (Baird et al., 1988). It shows that under conditions of good ascertainment, the overall ®gures are similar and are of the order of about 6±7% in live births (or 2± 3% if only major CAs i.e. lethal and severe ones are considered). 2.2.2. Aetiological heterogeneities (16) A small proportion of many of the CAs shows mendelian transmission [e.g. cleft lipcleft palate found as part of the autosomal dominant conditions Ð Van der Woude syndrome and EEC syndrome (ectrodactyly-ectodermal dysplasiaclefting)]Ð and occipital encephalocele as one feature of the autosomal recessive Meckel syndrome (see McKusick, 1994). A number of congenital cardiovascular malformaTable 2.1 A comparison of birth prevalences of congenital abnormalities in Hungary 1970±1981 (Czeizel and Sankaranarayanan, 1984) and British Columbia 1974±1983 (Baird et al., 1988) Prevalence per 1000 live births ICD codea
Type of abnormality
Hungary
British Columbiab
740±742 743 744 745±747 748 749 750±751 752±753 754±756 757 758 759
Central nervous system Eye Ear, face, and neck Heart and circulatory system Respiratory system Cleft lipcleft plate Other parts of digestive system Urogenital system Musculoskeletal system Integument disorders Chromosomal anomalies Other unspeci®ed disorders
2.2 0.3 0.5 7.9 0.3 1.5 2.8 9.1 31.3c 0.7 1.3 2.0
2.3 1.2 1.8 10.5 1.5 1.7 6.3 9.0 17.4 2.4 1.3 0.9
Total
740±759
59.9
52.8d
550 227±228
Inguinal hernia Congenital tumors
11.0 0.1
7.9d ±
71.0
60.7d
Grand total a
Based on WHO (1977). Most of these rates are based on total diagnoses and therefore have been adjusted downward by a factor of 0.8; see Baird et al. (1988) for details. c Prevalence would be 5.5 if congenital dislocation of the hip were excluded. d Based on actual cases, and not adjusted. b
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tions is found in association with dierent chromosomal abnormalities (Schinzel, 1983) as well as with foetal alcohol syndrome (Hanson, 1990). (17) The British Columbia (Baird et al, 1988) and Hungarian (Czeizel et al., 1993) estimates of the relative proportions of CAs due to single gene mutations, chromosomal anomalies, and environmental (including maternal) factors are summarised in Tables 2.2 and 2.3. In British Columbia, Table 2.2, Table 2.2 Classi®cation by aetiology of congenital abnormalities (ICD 740±789)a in the British Columbia study of Baird et al. (1988) Cases/millionb
% of grand total (I±V)
% of those with genetic aetiology (I±IV)
I Mendelian II Chromosomal III Multifactorial IV Genetics unknown Sub-total genetic V Non-genetic + unknown aetiologye
1098.2 1845.4 23,076.0c 564.6d 26,584.2 26,224.0f
2.1 3.5 43.7 1.1 50.4 49.6
4.1 6.9 86.8 2.1 100.0
Grand total
52,808.2
100.0
Category
a Numbers listed in Chapter XIV of the International Classi®cation of Diseases (1977); ICD numbers 740±759. b Sum of the highest individual rates for the decades 1952±1963, 1964±1973 and 1974±1983; see Baird et al. (1988) for details. c Also includes conditions other than those listed under ICD 740±759. d Sum for the decade (1952±1963) showing the highest rate; these are judged to have a genetic basis, but the precise mode of inheritance could not be determined. e For about 8%, no aetiology of the types I±IV could be assigned. f Arrived at by subtraction from the grand total.
Table 2.3 Classi®cation by aetiology of congenital abnormalities (ICD 740±749) in Hungary (Czeizel et al., 1993) Category
Birth prevalence per 1000
% of grand total (I±V)
% of those with genetic aetiology (I±IV)
I Mendelian II Chromosomal III Multifactorial IV Genetics unknown
3.6 3.0 45.3 ±
5.5 4.6 69.7 ±
6.9 5.8 87.3 ±
Sub-total genetic
51.9
79.8
100.0
V Non-genetic + unknown aetiology Teratogens Maternal factors Unknown aetiology
2.0 0.4 10.7
9 3.1 = 0.6 20.0 16.6 ;
Grand total
65.0
100.0 19
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. of the total incidence of 5.3%, one-half of CAs is judged to be due to nongenetic (e.g. prenatal infections, known teratogen, or birth trauma), and unknown causes; . of the remaining one-half, the vast majority (86.8%; column 4) is multifactorial; and . the mendelian, chromosomal, and `genetics unknown' categories account for, respectively, 4.1, 6.9, and 2.1%, of CAs with a genetic basis. The estimates for Hungary (Table 2.3) are in good agreement with the above in showing similar relative proportions of mendelian, chromosomal, and multifactorial categories (among those with genetic aetiologies); however, the `non-genetic and unknown' category is much smaller (about 20% in Hungary versus 50% in British Columbia). (18) Aetiological diagnoses of selected CAs in the British Columbia study are shown in Table 2.4. It is clear that in this population (i) a predominant majority of the CAs is multifactorial and (ii) a small proportion of each of these has a mendelian or chromosomal aetiology; notable among the latter are cleft lipcleft palate (about 1% mendelian and 1.7%, chromosomal) and hypospadias (about 1% mendelian or chromosomal). 2.3. Isolated congenital abnormalities 2.3.1. Epidemiological features (19) The Hungarian data on well-studied isolated CAs and some of their epidemiological features are presented in Table 2.5. As can be seen, . the sex-ratio departs from unity in most CAs; . there are racial/ethnic, regional, or seasonal dierences in the incidence of some CAs; and . the concordance rates in monozygotic co-twins is higher [from about 15% (undescended testicles) to about 80% (congenital dislocation of the hip) in Hungary] than those in dizygotic twins (0 to 14%), but not 100%. For cardiovascular malformations in general, both the Hungarian and literature data (Carter, 1976; Nora et al., 1991) suggest concordance between monozygotic cotwins is of the order of 15±20%. For dizygotic co-twins the rates are much lower. 2.3.2. Recurrence risks (20) Data on the birth frequencies of isolated CAs in relatives of index patients are given in Table 2.6. First, the frequency of aected ®rst-degree relatives of a proband is many times (5 to 50-fold) that of the general population. Second, there is a sharp decrease in the proportion aected as one passes from ®rst to second to third degree 20
Table 2.4 Aetiological diagnosis of some common congenital abnormalities in the British Columbia study of Baird et al. (1988). Adapted from Anderson et al. (1987)a Congenital abnormality
a b c
Total
AD
AR
XL
0
3
0
8 0 9 7 1 5
13 2 11 7 0 5
1 0 1 2 0 2
Chromosomalc
Total
Multifactorial
Genetics unknown
Non-genetic
Unknown aetiology
Total
A
X
3
1
0
1
1044
9
138
17
1212
22 2 21 16 1 12
38 1 16 8 3 5
1 0 0 0 0 2
39 1 16 8 3 7
1949 1941 5069 2909 768 0
70 1 61 28 0 17
239 50 259 124 30 1651
59 6 129 50 4 265
2378 2001 5655 3135 806 1952
For those diagnosed in decades 1952±1963, 1964±1973 and 1974±1983. AD, autosomal dominant; AR, autosomal recessive; XL, X-linked. A, autosomal; X, X-chromosomal abnormalities.
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Anencephaly, spina bi®da, encephalocele Cleft lip palate Pyloric stenosis Clubfoot Cong. dislocation of hip Cong. dislocatable hip Hypospadias
Mendelianb
Table 2.5 Some epidemiological features of selected isolated congenital abnormalities (CAs) in Hungary. Adapted from Czeizel and Tusnady (1984) CA entity
Prevalence per 100 births
a
Sex ratio (M:F)
Concordancef rates (%) in monozygotic (MZ) and dizygotic (DZ) twins MZ
DZ
Other features
0.29
1:15
28.7
0
Regional+seasonal variations in birth frequency; signi®cantly less frequent in Oriental and African peoples, more frequent in Sikhs of Northern India and in Egypt; high still-birth and infant mortality rates; higher ASB prevalence among ®rst-borns; more advanced maternal age
Cleft lip with or without cleft palate (CLCP)
0.10a
1.8:1.0
20.0
0
Isolated CLCP has about 1:2 ratio of CL and CLCP; CL 3 more common on the left side; higher birth frequencies in Japan and lower ones in African people; higher birth prevalence with advanced maternal age
Congenital hypertrophic pyloric stenosis (CHPS)
0. 15b
4:1 to 5:1
±
±
Lower birth prevalence in African people (5±10/104), Orientals (1±5/104), and still lower in Filipinos (below 1/104)
Ventricular septal defect (VSD)
0.15b
1:1.2
22.2
0
Accounts for 25±30% of all cases of congenital cardiovascular malformations
Congenital dislocation of the hip (CDH)
2.8b
1:5 to 1:8
83.3
13.6
1.30b,c 0.13b
Higher birth prevalence in Bretagne (France); also in American Indians and Lapps; higher birth prevalence in winter months, breech deliveries, and among ®rst-borns
2:1
50.8
3.5
Half the cases of congenital are bilateral; more frequent among twins; pre-term births slightly more common and breech presentations 3x more frequent; about 3 more prevalent among gypsies
Congenital inguina hernia (CIH)
1.14b
9:1
46.2
8.3
More common in winter births; predominance of right side involvement; advanced maternal age
Simple hypospadias (SH)
0.44b,d
Only in males
28.7
0
Lower birth weights and higher proportion of ®rst-borns among index cases
Undescended testicle(s) (UT)
1.35b,d
Only in males
15.4
0
More UT boys born between February and June; 2/3 of cases unilateral with the right side aected more often than the left
Structural talipes equinovarus (STEV)
a b c d e f
0.80e
Among total (i.e still and live) births. Among live births. Recent ®gure. In male births. Prevalence at one year of age. Concordance rates published in the literature are dierent to some extent, but in common with Hungarian data, show higher rates for MZ twins.
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22
Anencephaly, spina bi®da cystica and encephalecele (ASB)
Table 2.6 Increased prevalence of isolated congenital abnormalities in relatives of index patients. Adapted from Czeizel and Tusnady (1984) CA entitya
a b c d
0.29 0.10 0.15 0.15 2.8 0.13 1.14 0.44 1.35
Prevalence in relatives of index patients Parents (1st degree)
Sibs (1st degree)
Uncles±aunts (2nd degree)
First cousins (3rd degree)
%
Increaseb
%
Increaseb
%
Increaseb
%
Increaseb
± 1.9 1.4 ± 2.3 2.1 2.3 5.7 3.7 4.8
± 19 9 ± 0.8 0.8 18 5 8 4
2.1 4.8 6.3 1.7 13.8 14.0 5.6 10.1 4.8 6.7
7 48 42 11 5 5 43 9 11 5
0.19 0.72 0.25 0.69 1.37 1.17 0.55 6.03 0.77 0.62
0.6 7.2 1.7 4.6 0.5 0.4 4.2 5.3 1.7 0.5
0.26 0.33 0.72 0.79 6.13 4.72 1.09 7.62 0.48 1.04
0.9 3.3 4.8 5.3 2.2 l.7 8.4 6.7 11 0.8
For the abbreviations used, see Table 2.5. Increase relative to the population prevalence. Budapest study. BeÂkeÂs county study.
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ASB CLCP CHPS VSD CDHc CDHd STEV CIH SH (in males) UT (in males)
Population prevalence (in %)
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relatives and third, the relative increase in risk (i.e. relative to the birth frequency in the population) is more marked with low birth frequency. Thus, for instance, in the case of congenital dislocation of the hip (birth frequency of 2.8%), the risk to sibs is 13.8%, which is higher by a factor of 5; for cleft lipcleft palate, with a lower birth frequency of 0.10%, the risk to sibs is 4.8%, which represents an increase by a factor of 48. (21) The recurrence risks in relatives also depends on the number of other aected family members, severity of the condition in the index case, and whether one sex is more frequently aected than the other. Thus for instance, the risk to ®rst-degree relatives of an index case (Table 2.7) increases when he or she has already at least one aected ®rst-degree relative. When the index case is of the more rarely aected sex, the proportion of aected relatives is generally higher (Table 2.8). In Hungary, congenital hypertrophic pyloric stenosis has a birth frequency of 0.07% in females and 0.22% in males. The risk to brothers of aected females is about 20%, which is much higher than the value of about 4% for the brothers of aected males (Czeizel and Tusnady, 1984). These estimates are comparable to those for the UK reported by Carter (1976), for brothers and sisters of male and female subjects, as well as for their sons and daughters. (22) The above situation however, is not obtained in the case of some other CAs (see Table 2.8). For instance, with cleft lipcleft palate, which has a higher incidence in males (0.13%) than in females (0.08%), the risk to brothers of an aected male is about 11% whereas that to brothers of an aected female is only about 1% (Czeizel and Tusnady, 1984). For ventricular septal defect (for which sex-dierence in birth frequency in the population is small), the risk to sibs of aected females is higher (by a factor of 1.5 to 2) relative to that of sibs of aected males. In the data from various studies summarised in Nora et al., (1991; their Table 4-5), this tendency (i.e. higher risk in ospring of females) is seen, not only for ventricular septal defect, but for other cardiovascular malformations as well.
Table 2.7 Recurrence risks with dierent numbers of previously aected sibs (and normal parents) (Czeizel and Tusnady, 1984) CA entitya
ASB CLCP CHPS VSD CDH STEV CIH a b
Aected sibs (all values in %) 0b
1
2
3
0.29 0.10 0.15 0.15 2.31 0.13 0.78
3.7 2.7 3.3 1.7 10.5 2.1 6.0
10.1 8.4 9.3 5.7 19.8 6.1 12.6
16.9 15.1 15.8 11.2 26.9 11.3 18.8
For the abbreviations used, see Table 2.5. Same as the population risk. 24
ICRP Publication 83 Table 2.8 In¯uence of sex of the index patient on the risk to relatives of isolated congenital abnormalities (Czeizel and Tusnady, 1984) CA entitya
ASB CLCP CPS VSD CDHc CDHd STEV CIH a b c d
Sex of index case
Sex-speci®c prevalence (%)
M F M F M F M F M F M F M F M F
0.22 0.36 0.13 0.08 0.22 0.07 0.14 0.16 1.20 3.90 0.81 5.06 0.17 0.08 1.89 0.25
Brother fold % 1.0 2.4 11.2 1.3 4.2 20.0 0.8 2.1 16.0 6.9 9.1 6.7 6.6 6.9 12.9 5.7
Sister fold
Increaseb 4 7 86 16 19 286 6 15 13 2 11 1 39 86 7 23
% 2.3 2.3 ± 4.5 5.3 3 1.8 2.5 15.9 19.9 33.3 18.7 1.7 10.0 1.8 7.7
Increaseb 11 6 ± 56 75 ± 11 15 13 5 41 4 10 125 1 31
For the abbreviations used, see Table 2.5. Increase relative to the population prevalence. Budapest study. BeÂkeÂs county study.
2.4. Impact of advances in medicine on the incidence of congenital abnormalities (23) Czeizel (1994) made an analysis of the data on isolated CAs in Hungary from the standpoint of how advances in medicine during the past few decades have improved survival and reproduction of those aicted with some CAs. The ®ndings from this analysis have relevance in the context of estimating selection dierentials (considered in Chapter 8 on models for risk estimation). (24) For example, congenital hypertrophic pyloric stenosis was a lethal abnormality before the introduction of the Ramstedt operation (pyloromyotomy) in the early 1920s. At present, there is little or no selection against this condition. The birth frequency of congenital dislocation of the hip had been quite high in the early 1940s (about 1% of school-age girls had this abnormality) and females had a low chance of getting married and thus the selection was nearly complete. After the introduction of neonatal orthopaedic screening, the estimate of its birth incidence was extremely high (the ®gures in the 1970s were of the order of about 3%; see Table 2.5), but over-diagnosis of borderline cases was a probable cause. The use of stricter criteria in recent years has resulted in a lower birth frequency (about 1.4%). Progress in secondary prevention has been substantial owing to early diagnosis of liability to develop this abnormality and early treatment. 25
ICRP Publication 83
(25) At present, congenital cardiovascular malformations represent one of the major public health problems in Hungary (total birth frequency of about 10.5/1000). Before the introduction of the surgical correction, early mortality was very high, about 80%. Now it is only about 30%. CAs of the male reproductive systemÐ mainly simple hypospadias and undescended testicles Ð show an increasing trend in Hungary (birth frequency of about 2.2/1000 in the 1970s increasing to 3.3/1000 in the 1980s). In parallel with this, there is a decrease in the quality of semen (both sperm concentration and motility) and an increase in the incidence of testicular cancers (3±4). The recurrence risk is about 5% for simple hypospadias although in the past this could not be detected because of infertility. A similar situation holds for undescended testicles. Eective treatment of cases of the above two abnormalities has improved their fertility and the majority now have children. (26) Neural tube defects (anencephaly, encephalocele, spina bi®da cystica/aperta) are among the most common and serious CA groups, with a prevalence of about 3/ 1000 total births. Until the late l950s, all anencephalic and encephalic newborns and 98% of those with spina bi®da cystica died. In the early l960s, early surgery and active treatment were introduced in cases of spina bi®da and encephalocele with signi®cant success. About 60% of cases survived, but most survivors had multiple and long-term disabilities. In the 1980s, the introduction and ecacy of maternal serum alpha-foetoprotein and ultrasound screening, in addition to amniotic alphafoetoprotein and other examinations have had a substantial eect (secondary prevention through termination of aected foetuses). In the 1990s, the introduction of periconceptional multivitamin/folic acid supplementation has shown that primary prevention of neural tube defects (reduction by about 50%) is possible (e.g. MRC, 1991; Czeizei and Dudas, 1992; Czeizel et al., 1993; Czeizel, 1995). (27) It is thus clear that for a number of CAs selective pressures, which in the past would have either eliminated (through early mortality) or caused prereproductive deaths of individuals who have CAs are far less now as a result of advances in medicine. 2.5. Summary (28) Congenital abnormalities arise as a result of developmental errors and are present at birth. In well-conducted studies, their birth frequency has been estimated to be of the order of about 6 to 7%. They are aetiologically heterogeneous. While it is clear that both genetic and shared environmental factors are important in their origin, the nature of these factors and the mechanisms involved, remain to be elucidated. Most of their attributes (occurrence in higher frequencies among the relatives of aected individuals than in the general population and higher, but always much lower than 100% concordance rates in monozygotic twins than in dizygotic twins, sex dierences in incidence, seasonal variations in birth frequencies etc.,) are not readily explained on the basis of simple mendelian patterns of inheritance. Advances in medicine during the past few decades have improved survival and reproduction of those aicted with some congenital abnormalities. 26
ICRP Publication 83
al., 1988b; Brent, 1986; Baird et al., 1988; reviewed in Sankaranarayanan et al., 1994). The estimates in these and other studies not referred to above, vary widely from about 1% in live births to a high of about 8.5% in total births (i.e. still+live births) depending on, among others, de®nition, classi®cation, and diagnostic criteria, entities included, method of ascertainment, duration of follow-up of live-born children, sample sizes, etc. (15) Table 2.1 compares the birth frequency estimates of CAs in Hungary (Czeizel and Sankaranarayanan, 1984) with those in the Canadian province of British Columbia (Baird et al., 1988). It shows that under conditions of good ascertainment, the overall ®gures are similar and are of the order of about 6±7% in live births (or 2± 3% if only major CAs i.e. lethal and severe ones are considered). 2.2.2. Aetiological heterogeneities (16) A small proportion of many of the CAs shows mendelian transmission [e.g. cleft lipcleft palate found as part of the autosomal dominant conditions Ð Van der Woude syndrome and EEC syndrome (ectrodactyly-ectodermal dysplasiaclefting)]Ð and occipital encephalocele as one feature of the autosomal recessive Meckel syndrome (see McKusick, 1994). A number of congenital cardiovascular malformaTable 2.1 A comparison of birth prevalences of congenital abnormalities in Hungary 1970±1981 (Czeizel and Sankaranarayanan, 1984) and British Columbia 1974±1983 (Baird et al., 1988) Prevalence per 1000 live births ICD codea
Type of abnormality
Hungary
British Columbiab
740±742 743 744 745±747 748 749 750±751 752±753 754±756 757 758 759
Central nervous system Eye Ear, face, and neck Heart and circulatory system Respiratory system Cleft lipcleft plate Other parts of digestive system Urogenital system Musculoskeletal system Integument disorders Chromosomal anomalies Other unspeci®ed disorders
2.2 0.3 0.5 7.9 0.3 1.5 2.8 9.1 31.3c 0.7 1.3 2.0
2.3 1.2 1.8 10.5 1.5 1.7 6.3 9.0 17.4 2.4 1.3 0.9
Total
740±759
59.9
52.8d
550 227±228
Inguinal hernia Congenital tumors
11.0 0.1
7.9d ±
71.0
60.7d
Grand total a
Based on WHO (1977). Most of these rates are based on total diagnoses and therefore have been adjusted downward by a factor of 0.8; see Baird et al. (1988) for details. c Prevalence would be 5.5 if congenital dislocation of the hip were excluded. d Based on actual cases, and not adjusted. b
18
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tions is found in association with dierent chromosomal abnormalities (Schinzel, 1983) as well as with foetal alcohol syndrome (Hanson, 1990). (17) The British Columbia (Baird et al, 1988) and Hungarian (Czeizel et al., 1993) estimates of the relative proportions of CAs due to single gene mutations, chromosomal anomalies, and environmental (including maternal) factors are summarised in Tables 2.2 and 2.3. In British Columbia, Table 2.2, Table 2.2 Classi®cation by aetiology of congenital abnormalities (ICD 740±789)a in the British Columbia study of Baird et al. (1988) Cases/millionb
% of grand total (I±V)
% of those with genetic aetiology (I±IV)
I Mendelian II Chromosomal III Multifactorial IV Genetics unknown Sub-total genetic V Non-genetic + unknown aetiologye
1098.2 1845.4 23,076.0c 564.6d 26,584.2 26,224.0f
2.1 3.5 43.7 1.1 50.4 49.6
4.1 6.9 86.8 2.1 100.0
Grand total
52,808.2
100.0
Category
a Numbers listed in Chapter XIV of the International Classi®cation of Diseases (1977); ICD numbers 740±759. b Sum of the highest individual rates for the decades 1952±1963, 1964±1973 and 1974±1983; see Baird et al. (1988) for details. c Also includes conditions other than those listed under ICD 740±759. d Sum for the decade (1952±1963) showing the highest rate; these are judged to have a genetic basis, but the precise mode of inheritance could not be determined. e For about 8%, no aetiology of the types I±IV could be assigned. f Arrived at by subtraction from the grand total.
Table 2.3 Classi®cation by aetiology of congenital abnormalities (ICD 740±749) in Hungary (Czeizel et al., 1993) Category
Birth prevalence per 1000
% of grand total (I±V)
% of those with genetic aetiology (I±IV)
I Mendelian II Chromosomal III Multifactorial IV Genetics unknown
3.6 3.0 45.3 ±
5.5 4.6 69.7 ±
6.9 5.8 87.3 ±
Sub-total genetic
51.9
79.8
100.0
V Non-genetic + unknown aetiology Teratogens Maternal factors Unknown aetiology
2.0 0.4 10.7
9 3.1 = 0.6 20.0 16.6 ;
Grand total
65.0
100.0 19
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. of the total incidence of 5.3%, one-half of CAs is judged to be due to nongenetic (e.g. prenatal infections, known teratogen, or birth trauma), and unknown causes; . of the remaining one-half, the vast majority (86.8%; column 4) is multifactorial; and . the mendelian, chromosomal, and `genetics unknown' categories account for, respectively, 4.1, 6.9, and 2.1%, of CAs with a genetic basis. The estimates for Hungary (Table 2.3) are in good agreement with the above in showing similar relative proportions of mendelian, chromosomal, and multifactorial categories (among those with genetic aetiologies); however, the `non-genetic and unknown' category is much smaller (about 20% in Hungary versus 50% in British Columbia). (18) Aetiological diagnoses of selected CAs in the British Columbia study are shown in Table 2.4. It is clear that in this population (i) a predominant majority of the CAs is multifactorial and (ii) a small proportion of each of these has a mendelian or chromosomal aetiology; notable among the latter are cleft lipcleft palate (about 1% mendelian and 1.7%, chromosomal) and hypospadias (about 1% mendelian or chromosomal). 2.3. Isolated congenital abnormalities 2.3.1. Epidemiological features (19) The Hungarian data on well-studied isolated CAs and some of their epidemiological features are presented in Table 2.5. As can be seen, . the sex-ratio departs from unity in most CAs; . there are racial/ethnic, regional, or seasonal dierences in the incidence of some CAs; and . the concordance rates in monozygotic co-twins is higher [from about 15% (undescended testicles) to about 80% (congenital dislocation of the hip) in Hungary] than those in dizygotic twins (0 to 14%), but not 100%. For cardiovascular malformations in general, both the Hungarian and literature data (Carter, 1976; Nora et al., 1991) suggest concordance between monozygotic cotwins is of the order of 15±20%. For dizygotic co-twins the rates are much lower. 2.3.2. Recurrence risks (20) Data on the birth frequencies of isolated CAs in relatives of index patients are given in Table 2.6. First, the frequency of aected ®rst-degree relatives of a proband is many times (5 to 50-fold) that of the general population. Second, there is a sharp decrease in the proportion aected as one passes from ®rst to second to third degree 20
Table 2.4 Aetiological diagnosis of some common congenital abnormalities in the British Columbia study of Baird et al. (1988). Adapted from Anderson et al. (1987)a Congenital abnormality
a b c
Total
AD
AR
XL
0
3
0
8 0 9 7 1 5
13 2 11 7 0 5
1 0 1 2 0 2
Chromosomalc
Total
Multifactorial
Genetics unknown
Non-genetic
Unknown aetiology
Total
A
X
3
1
0
1
1044
9
138
17
1212
22 2 21 16 1 12
38 1 16 8 3 5
1 0 0 0 0 2
39 1 16 8 3 7
1949 1941 5069 2909 768 0
70 1 61 28 0 17
239 50 259 124 30 1651
59 6 129 50 4 265
2378 2001 5655 3135 806 1952
For those diagnosed in decades 1952±1963, 1964±1973 and 1974±1983. AD, autosomal dominant; AR, autosomal recessive; XL, X-linked. A, autosomal; X, X-chromosomal abnormalities.
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21
Anencephaly, spina bi®da, encephalocele Cleft lip palate Pyloric stenosis Clubfoot Cong. dislocation of hip Cong. dislocatable hip Hypospadias
Mendelianb
Table 2.5 Some epidemiological features of selected isolated congenital abnormalities (CAs) in Hungary. Adapted from Czeizel and Tusnady (1984) CA entity
Prevalence per 100 births
a
Sex ratio (M:F)
Concordancef rates (%) in monozygotic (MZ) and dizygotic (DZ) twins MZ
DZ
Other features
0.29
1:15
28.7
0
Regional+seasonal variations in birth frequency; signi®cantly less frequent in Oriental and African peoples, more frequent in Sikhs of Northern India and in Egypt; high still-birth and infant mortality rates; higher ASB prevalence among ®rst-borns; more advanced maternal age
Cleft lip with or without cleft palate (CLCP)
0.10a
1.8:1.0
20.0
0
Isolated CLCP has about 1:2 ratio of CL and CLCP; CL 3 more common on the left side; higher birth frequencies in Japan and lower ones in African people; higher birth prevalence with advanced maternal age
Congenital hypertrophic pyloric stenosis (CHPS)
0. 15b
4:1 to 5:1
±
±
Lower birth prevalence in African people (5±10/104), Orientals (1±5/104), and still lower in Filipinos (below 1/104)
Ventricular septal defect (VSD)
0.15b
1:1.2
22.2
0
Accounts for 25±30% of all cases of congenital cardiovascular malformations
Congenital dislocation of the hip (CDH)
2.8b
1:5 to 1:8
83.3
13.6
1.30b,c 0.13b
Higher birth prevalence in Bretagne (France); also in American Indians and Lapps; higher birth prevalence in winter months, breech deliveries, and among ®rst-borns
2:1
50.8
3.5
Half the cases of congenital are bilateral; more frequent among twins; pre-term births slightly more common and breech presentations 3x more frequent; about 3 more prevalent among gypsies
Congenital inguina hernia (CIH)
1.14b
9:1
46.2
8.3
More common in winter births; predominance of right side involvement; advanced maternal age
Simple hypospadias (SH)
0.44b,d
Only in males
28.7
0
Lower birth weights and higher proportion of ®rst-borns among index cases
Undescended testicle(s) (UT)
1.35b,d
Only in males
15.4
0
More UT boys born between February and June; 2/3 of cases unilateral with the right side aected more often than the left
Structural talipes equinovarus (STEV)
a b c d e f
0.80e
Among total (i.e still and live) births. Among live births. Recent ®gure. In male births. Prevalence at one year of age. Concordance rates published in the literature are dierent to some extent, but in common with Hungarian data, show higher rates for MZ twins.
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22
Anencephaly, spina bi®da cystica and encephalecele (ASB)
Table 2.6 Increased prevalence of isolated congenital abnormalities in relatives of index patients. Adapted from Czeizel and Tusnady (1984) CA entitya
a b c d
0.29 0.10 0.15 0.15 2.8 0.13 1.14 0.44 1.35
Prevalence in relatives of index patients Parents (1st degree)
Sibs (1st degree)
Uncles±aunts (2nd degree)
First cousins (3rd degree)
%
Increaseb
%
Increaseb
%
Increaseb
%
Increaseb
± 1.9 1.4 ± 2.3 2.1 2.3 5.7 3.7 4.8
± 19 9 ± 0.8 0.8 18 5 8 4
2.1 4.8 6.3 1.7 13.8 14.0 5.6 10.1 4.8 6.7
7 48 42 11 5 5 43 9 11 5
0.19 0.72 0.25 0.69 1.37 1.17 0.55 6.03 0.77 0.62
0.6 7.2 1.7 4.6 0.5 0.4 4.2 5.3 1.7 0.5
0.26 0.33 0.72 0.79 6.13 4.72 1.09 7.62 0.48 1.04
0.9 3.3 4.8 5.3 2.2 l.7 8.4 6.7 11 0.8
For the abbreviations used, see Table 2.5. Increase relative to the population prevalence. Budapest study. BeÂkeÂs county study.
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23
ASB CLCP CHPS VSD CDHc CDHd STEV CIH SH (in males) UT (in males)
Population prevalence (in %)
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relatives and third, the relative increase in risk (i.e. relative to the birth frequency in the population) is more marked with low birth frequency. Thus, for instance, in the case of congenital dislocation of the hip (birth frequency of 2.8%), the risk to sibs is 13.8%, which is higher by a factor of 5; for cleft lipcleft palate, with a lower birth frequency of 0.10%, the risk to sibs is 4.8%, which represents an increase by a factor of 48. (21) The recurrence risks in relatives also depends on the number of other aected family members, severity of the condition in the index case, and whether one sex is more frequently aected than the other. Thus for instance, the risk to ®rst-degree relatives of an index case (Table 2.7) increases when he or she has already at least one aected ®rst-degree relative. When the index case is of the more rarely aected sex, the proportion of aected relatives is generally higher (Table 2.8). In Hungary, congenital hypertrophic pyloric stenosis has a birth frequency of 0.07% in females and 0.22% in males. The risk to brothers of aected females is about 20%, which is much higher than the value of about 4% for the brothers of aected males (Czeizel and Tusnady, 1984). These estimates are comparable to those for the UK reported by Carter (1976), for brothers and sisters of male and female subjects, as well as for their sons and daughters. (22) The above situation however, is not obtained in the case of some other CAs (see Table 2.8). For instance, with cleft lipcleft palate, which has a higher incidence in males (0.13%) than in females (0.08%), the risk to brothers of an aected male is about 11% whereas that to brothers of an aected female is only about 1% (Czeizel and Tusnady, 1984). For ventricular septal defect (for which sex-dierence in birth frequency in the population is small), the risk to sibs of aected females is higher (by a factor of 1.5 to 2) relative to that of sibs of aected males. In the data from various studies summarised in Nora et al., (1991; their Table 4-5), this tendency (i.e. higher risk in ospring of females) is seen, not only for ventricular septal defect, but for other cardiovascular malformations as well.
Table 2.7 Recurrence risks with dierent numbers of previously aected sibs (and normal parents) (Czeizel and Tusnady, 1984) CA entitya
ASB CLCP CHPS VSD CDH STEV CIH a b
Aected sibs (all values in %) 0b
1
2
3
0.29 0.10 0.15 0.15 2.31 0.13 0.78
3.7 2.7 3.3 1.7 10.5 2.1 6.0
10.1 8.4 9.3 5.7 19.8 6.1 12.6
16.9 15.1 15.8 11.2 26.9 11.3 18.8
For the abbreviations used, see Table 2.5. Same as the population risk. 24
ICRP Publication 83 Table 2.8 In¯uence of sex of the index patient on the risk to relatives of isolated congenital abnormalities (Czeizel and Tusnady, 1984) CA entitya
ASB CLCP CPS VSD CDHc CDHd STEV CIH a b c d
Sex of index case
Sex-speci®c prevalence (%)
M F M F M F M F M F M F M F M F
0.22 0.36 0.13 0.08 0.22 0.07 0.14 0.16 1.20 3.90 0.81 5.06 0.17 0.08 1.89 0.25
Brother fold % 1.0 2.4 11.2 1.3 4.2 20.0 0.8 2.1 16.0 6.9 9.1 6.7 6.6 6.9 12.9 5.7
Sister fold
Increaseb 4 7 86 16 19 286 6 15 13 2 11 1 39 86 7 23
% 2.3 2.3 ± 4.5 5.3 3 1.8 2.5 15.9 19.9 33.3 18.7 1.7 10.0 1.8 7.7
Increaseb 11 6 ± 56 75 ± 11 15 13 5 41 4 10 125 1 31
For the abbreviations used, see Table 2.5. Increase relative to the population prevalence. Budapest study. BeÂkeÂs county study.
2.4. Impact of advances in medicine on the incidence of congenital abnormalities (23) Czeizel (1994) made an analysis of the data on isolated CAs in Hungary from the standpoint of how advances in medicine during the past few decades have improved survival and reproduction of those aicted with some CAs. The ®ndings from this analysis have relevance in the context of estimating selection dierentials (considered in Chapter 8 on models for risk estimation). (24) For example, congenital hypertrophic pyloric stenosis was a lethal abnormality before the introduction of the Ramstedt operation (pyloromyotomy) in the early 1920s. At present, there is little or no selection against this condition. The birth frequency of congenital dislocation of the hip had been quite high in the early 1940s (about 1% of school-age girls had this abnormality) and females had a low chance of getting married and thus the selection was nearly complete. After the introduction of neonatal orthopaedic screening, the estimate of its birth incidence was extremely high (the ®gures in the 1970s were of the order of about 3%; see Table 2.5), but over-diagnosis of borderline cases was a probable cause. The use of stricter criteria in recent years has resulted in a lower birth frequency (about 1.4%). Progress in secondary prevention has been substantial owing to early diagnosis of liability to develop this abnormality and early treatment. 25
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(25) At present, congenital cardiovascular malformations represent one of the major public health problems in Hungary (total birth frequency of about 10.5/1000). Before the introduction of the surgical correction, early mortality was very high, about 80%. Now it is only about 30%. CAs of the male reproductive systemÐ mainly simple hypospadias and undescended testicles Ð show an increasing trend in Hungary (birth frequency of about 2.2/1000 in the 1970s increasing to 3.3/1000 in the 1980s). In parallel with this, there is a decrease in the quality of semen (both sperm concentration and motility) and an increase in the incidence of testicular cancers (3±4). The recurrence risk is about 5% for simple hypospadias although in the past this could not be detected because of infertility. A similar situation holds for undescended testicles. Eective treatment of cases of the above two abnormalities has improved their fertility and the majority now have children. (26) Neural tube defects (anencephaly, encephalocele, spina bi®da cystica/aperta) are among the most common and serious CA groups, with a prevalence of about 3/ 1000 total births. Until the late l950s, all anencephalic and encephalic newborns and 98% of those with spina bi®da cystica died. In the early l960s, early surgery and active treatment were introduced in cases of spina bi®da and encephalocele with signi®cant success. About 60% of cases survived, but most survivors had multiple and long-term disabilities. In the 1980s, the introduction and ecacy of maternal serum alpha-foetoprotein and ultrasound screening, in addition to amniotic alphafoetoprotein and other examinations have had a substantial eect (secondary prevention through termination of aected foetuses). In the 1990s, the introduction of periconceptional multivitamin/folic acid supplementation has shown that primary prevention of neural tube defects (reduction by about 50%) is possible (e.g. MRC, 1991; Czeizei and Dudas, 1992; Czeizel et al., 1993; Czeizel, 1995). (27) It is thus clear that for a number of CAs selective pressures, which in the past would have either eliminated (through early mortality) or caused prereproductive deaths of individuals who have CAs are far less now as a result of advances in medicine. 2.5. Summary (28) Congenital abnormalities arise as a result of developmental errors and are present at birth. In well-conducted studies, their birth frequency has been estimated to be of the order of about 6 to 7%. They are aetiologically heterogeneous. While it is clear that both genetic and shared environmental factors are important in their origin, the nature of these factors and the mechanisms involved, remain to be elucidated. Most of their attributes (occurrence in higher frequencies among the relatives of aected individuals than in the general population and higher, but always much lower than 100% concordance rates in monozygotic twins than in dizygotic twins, sex dierences in incidence, seasonal variations in birth frequencies etc.,) are not readily explained on the basis of simple mendelian patterns of inheritance. Advances in medicine during the past few decades have improved survival and reproduction of those aicted with some congenital abnormalities. 26