Polygenic inheritance of certain common malformations

THE JOURNAL OF

PEDIATRICS MAY

MEDICAL

1 970

Volume 76

Number 5

PROGRESS

Polygenic inheritance of certain common malformations Evidence and empiric recurrence risk data Knowledge regarding the precise etiology o[ single common mal[ormations is inexact. However, presently available indirect evidence suggests that the combination o[ a number o[ genie [actors, or polygenie inheritance, is the most likely explanation [or the majority o[ them.

David W. Smith and

Jon M.

Aase

SEATTLE) W A S H .

T H ~. R ~ is a growing body of indirect evidence indicating that polygenic inheritance is a major factor in the etiology of mz/ny common single malformations which occur in otherwise normal individuals. Polygenic inheritance of a particular feature simply denotes that it is determined by the effects of many genes. POLYGENIC I N H E R I T A N C E OF NORMAL CHARACTERISTICS

Though it has often been assumed in earlier teaching that a given trait is transFrom the Dysmorphology Unit, Department o[ Pediatrics, University o[ Washington Medical School. Supported by a grant [rom the Children's Bureau.

mitted b y a single gene, no normal physical [eature in the human has been identified with the action of a single gene. Rather, it appears that usual morphologic features are determined by the combined effects of many genes. The theory of polygenic determination allows for the type of gradations which are apparent in the inheritance of such gross features as height and pigmentation of the skin. Environmental factors may also impose further variability: for example, the effects of nutrition upon eventual adult height, or the effect of sunlight upon skin pigmentation. Fundamentally, the polygenic theory is based on the probability that a morphologic feature is the result of the concerted effect of a number of genes, and that minor difVol. 76, No. 5, pp. 653-659

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Smith and Aase

The Journal of Pediatrics May 1970

ferences within individual genes of this group allow for variability in t h e ni~ture o f the characteristic which they determine. The spectrum of possible variations includes incomplete or otherwise abnormal morphogenesis resulting in malformation. ~.OLYGENIC I N H E R I T A N C E FOR CERTAIN COMMON MALFORMATIONS

The evidence for polygenic inheritance is entirely indirect and is based upon data of incidence in the general population and of familial recurrence of particular malformations., The anomalies listed in Table I each

occur with a frequency of 0.5 to 2 per 1,000 in Caucasian populations, and collectively account for about 47 per cent of babies with obvious malformations in early infancy. These data are derived from individuals with a single primary defect in morphogenesis who were otherwise normal; none of the following data are applicable to individuals with multiple primary defects. Frequency of defect in relatives. T h e probability of recurrence of certain defects in siblings of an affected individual when the parents are normal is shown in Table I. Though recurrence risks in the range of 2 to 5 per cent are relatively low, they are sub-

Table I. Empirically derived probabilities for recurrence of some common single malformations

Risk for recurrence of defect Risk of defect in offspring in siblings born subsequently of an affected individual (%) Defect to unaffected parents (%) Cleft lip plus or minus cleft palate 4.9 4.3

References 1, 2

Cleft palate alone

2.0

6.0

Clubfoot

2-8

4, 5

Anencephaly*

3.4

6, 7, 8

Meningomyelocele*

4.8

Dislocation of hip

3.5 (brothers 0.5, sisters 6.3)

Pyloric stenosis

3.2 (brothers 4.0, sisters 2.4)

3

Affected fathers 4.6; affected mothers 16.2

* F o r anencephaly or meningomyelocele there apl~ears to be about an equal recurrence risk that either anomaly m a y occur in subsequent siblings, since these anomMies seem to be linked etiologically.

Table II. Increased risk of relatives having the same malformation as a propositus (from Carter 5)

Incidence in general population Incidence in relatives vs. incidence in general population 1st degree: Relatives 2nd degree: Relatives 3rd degree: Relatives

Cleft lip plus or minus cleft palate

Congenital dislocation of hip

1/1,000

I I

Pylorie stenosis

Talipes equinovarus

Aneneephalymeningomyelocele

1/1,000

2/1,000

1/1,000

2/1,000

35x

40x

20x

20x

8x

7x

4x

5x

5x

--

3x

1.5x

2x

2x

2x

Volume 76 Number 5

Polygenic inheritance of common malformations

stantially above those of the general population. In Table I I the incidences of these defects in relatives of an affected individual are compared with the incidence in the general population. These findings of familial incidence are difficult to reconcile with single gene dominant or recessive inheritance but are compatible with a polygenic mode of inheritance. Concordance in twins. If one twin has a defect, one may ask what is the probability that the other twin will have the same type of defect? When both twins have the defect, they are said to be conc6rdant. Fig. 1 shows the frequency of concordance for dizygotic (nonidentical) versus presumed monozygotic (identical) twin sets. Of especial importance is the fact that the rate of concordance in dizygotic twins is comparable to that of siblings born of separate pregnancies. These data provide evidence against a major en-

NO. OF TWIN A N O M A L Y SETS C L E F T LIP & PALATE

67 19

CONGENITAL DISLOCATION OF HIP

112 29

CLUBFOOT PYLORIC STENOSIS

vironmental (intrauterine) factor in the etiology of these malformations. T h e frequency of concordance in monozygotic twin sets is 4 to 8 times that in dizygotic twin sets and thus provides evidence for a genetic mode of etiology for these defects. Yet the highest concordance rate for a single defect in identical twin sets, 40 per cent for cleft lip plus or minus cleft palate, demonstrates that given the same genetic background and similar intrauterine environment, the majority of monozygous twin sets are not concordant for these defects. This fact emphasizes the subtlety of the phenomena involved in the developmental pathology of these malformations, so subtle that one identical twin can be affected and the other normal. Influence of genetic background. Sex. The differences between X X and X Y genetic background illustrate genetic

PERCENTAGE OF TWIN-SETS CONCORDANT FOR ANOMALY

REFERENCE METRAKOS

r

al '~

11

IDELBERGER

134 ~ 40 45 ~ 14 ~

o

B~OK4 McKEOWN el- al la

,b

ab

4b

50%

Fig. 1. Concordance for certain single malformations in dizygotic (stippled bar) versus monozygotic (hatched bar) twins. 5, 10, 11 Proportion of Males vs. F e m a l e s

~

Pyloric StenosisClubfoot

5:1

.....

Cleft Lip*/- Palate V / / - - ~

Cleft Palate alone

Male

f i- /

. ~ / / / / /

~ , / ~ F /emale e//lej~

1:1.3

Meningomyelocele Anencephaly - - Cong. Disloc. H i p -

65 5

~. ~--'/~~"/~/~~

1:5.5

Fig. 2. Relative incidence of single malformations in the XY individual versus the XX one.

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Smith and Aase

The Journal o[ Pediatrics May 1970

factors which have appreciable effects on the occurrence of certain major malformations, none of which has aft dqual sex incidence (Fig. 2). These sex differences provide some of the best evidence for polygenic inheritance. Taking pyloric stenosis as an example, Carter s reasoned as follows: If it gengrally requires appreciably more genetic factors to allow for development of pyloric stenosis in the female than the male, then the affected female should be far more likely to pass on sufficient genetic factors to allow for an affected offspring. This is precisely what Carter found; the incidence of pyloric stenosis in offspring of affected females was about four times greater than that in offspring of affected males (Fig. 3). Cleft lip, which is twice as likely to be manifest in the male as in the reinMe, is another example of sex-influenced polygenic type of inheritance. The occurrence of cleft lip in offspring of females with this lesion is 6 per cent, in contrast to an occurrence rate of 2.8 per cent in offspring of males with this lesion2 Race. Numerous subtle genetic differences exist among racial groups. Racial differences in genetic endowment could be expected to alter the incidence of particular types of anomalies which are determined in a polygenie fashion. Such a variation is illustrated in Fig. 4. The incidence of a particular anomaly may vary considerably from one racial group

Percentage O f f s p r i n g 0 5 10 15 i

Affected Mothers

IIIIIlilt]llll

I

I

llllllllillllI)fl

- D a u g h t e r s ~17/62 11111

Affected Fat he rs

I

Affected 20 25

1

SO n s

191296

71274

Likelihood

of

Pyioric

Stenosis

Fig. 3. Comparative incidence of pyloric stenosis in offspring of mothers who had pyloric stenosls in infancy versus ~e incidence in offspring of similarly affected fathers. From Carter. 5

to another. For example, severe clubfoot is a common anomaly among Polynesians, and a rare one among Chinese. The racial patterns in Hawaii provided Chung 14 the opportunity to determine the effects of racial admixture on the occurrence of this anomaly (Fig. 5). His findings are compatible with a polygenic mode of determination for clubfoot in Hawaiians, with reduction in its incidence following racial admixture with the Chinese. A similar example was observed in respect to polydactyly in S~o Paulo, where Negroes had an incidence of 0.7 per cent, Caucasians 0.24 per cent, and Mulattos 0.52 per cent? 5 Variance in recurrence risk in relation to severity of malformation. Carter 5 has some limited data which support the following hypothesis: The more severe the degree of malformation, the greater the likelihood of recurrence of that defect. T h e risk for recurrence of cleft lip plus or minus cleft palate in subsequent siblings of a child with bilateral cleft is 5.7 per cent, as contrasted to a 2.5 per cent recurrence risk when the affected child has only a unilateral cleft lip. These data are also compatible with the polygenic hypothesis. Comment regarding environmental factors. Some indications of environmental effects have been noted in Scotland and England in studies of families with anencephaly-meningomyelocele; namely, seasonal variability ~ and social class differences? ~ However, no seasonal variability or social class differences were noted for these defects in Lebanon? s Birth order influences have also been noted, congenital dislocation of the hip and pyloric stenosis being more likely to occur in the firstbornJ The search for environmental components which can allow for expression of a common single malformation in man should obviously continue. However, present evidence suggests the concerted effect of polygenic factors as the predominant basis for the aforementioned defects. Furthermore, just as multiple minor genetic differences are difficult to individualize, so environmental components are likely to be multiple and subtle in

Volume 76

Polygenic inheritance o/ common malformations

Number 5

10o

90 .o~176 .ODD, i,**6 eoe*~ l,~ ~,ola o~o*o ,o~176

80 W (,.)

70

Z

W

a z

60

X

50

IZ W U

40

Q.

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XXX X xx X XX X XX X

XX

x

xx

X

xx

x

XX

x X X X xx

30

X

XX

X xx x X X

20

I ll X XX X Xl

10

JAPANESE

MUSCULO-SKELETAL

~-]

CENTRAL

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~

GASTRO-INTESTINAL

SWE DISH

SYSTEM

SYSTEM

SYSTEM

IRISH

INDIAN

CARDIO-VASCULAR

GENITO'URINARY

MULTIPLE

SYSTEM

SYSTEM

SYSTEMS

OTHERS

Fig. 4. Varying frequency of types of malformations among different racial groups. From Kolah and associates. 13

_

Incidence per 1000 Births

6- ~ f JJ / / J/ ~ 4- >~//~ f / / / /

Hawaiian

X

Hawaiian

Part-Haw. Part-Haw. • X Part-Haw. C h i n e s e

Chinese X Chinese

Cauc Cauc,

Fig. 5. T h e incidence of serious clubfoot deformity among individuals of variant racial background in Hawaii. From the study of Chung. 14

65 7

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Smith and Aase

character. The total factors interact to approach a threshold for a pa[ticular defect in morphogenesis, a threshold which is predominantly set by the genetic makeup of the individual. COUNSELING

The following is our current practice in the counseling of parents who have a child with one of the foregoing malformations. For purposes of perspective, certain aspects of nongenetic counsel are included. 1. The developmental pathology of the abnormality is explained, with emphasis upon the localized nature of the initial defect in morphogenesis. When possible, the lesions can be interpreted as having occurred prior to a certain time in gestation (as for cleft lip plus or minus cleft palate, 36 days; cleft palate, 60 ~tays; and meningomyelocele, 26 days). T h e parents then can be reassured that events occurring later in the pregnancy bore no causal relationship to the developmental defect. Such information often provides a good opportunity to allay the parents' fears about possible causative factors such as accidents, ingestion of drugs, or vaginal bleeding late in pregnancy. 2. The prognosis and management of the child are then discussed. When the single defect is of the type which, with repair, need not interfere with social acceptance or function, it is often helpful to tell the parents that the child is normal. For example, ,the parents of a baby with isolated cleft lip may be told, "Your child is normal, but the lip did not close completely; therefore it will be necessary to bring about the closure by plastic surgery." T h e purpose of this approach is to assist the parents in acceptance o f the child by putting the defect in perspective and not branding the whole child as malformed. 3. I t can be pointed out that morphogenesis is a genetically determined process in which numerous genes play a role in the development of a given structure. Explain that the set of genes derived from both parents did not allo w for full normal development of that particular structure in their

The Journal o[ Pediatrics May 1970

child. It is worthwhile to indicate how subtle is the threshold between normal and abnormal development for such single defects. 4. T h e parents can be given an indication of the likelihood of recurrence of the same defect in future offspring. With normal parents, the chance of a subsequent child inheriting a similar set of genes and having the same type of malformation, is of low magnitude 5 per cent or less for the common single defects. In giving this counsel the risk figures may be slightly increased when the defect in the present child is severe in degree, and degreased when the anomaly is mild in degree. The risk figures may be separately stated for the sex of the offspring, especially those for pyloric stenosis and congenital dislocation of the hip. If two offspring have been affected, the risk for subsequent children is two- to threefold greater than when there has been only one affected child. The risk of an affected individual having an affected offspring is of similar magnitude to the sibling recurrence risk (about 5 per cent). 5. Finally, the parents should be told that our present knowledge does not give a clear indication of any single environmental factor which is a known cause of one of the aforementioned anomalies. T h e purpose of such a statement is to allay any guilt feelings which the mother may have about the association between a particular event during the pregnancy and the occurrence of the defect. REFERENCES

1. Fogh-Andersen, P.: Inheritance of cleft lip and cleft palate, Copenhagen, 1942, Ejnar Munksgaard Forlag. 2. Woolf, C. M., Woolf, R. M., and Broadbent, T. R.: A genetic study of cleft lip and palate in Utah, Amer. J. Hum. Genet. 15: 209, 1963. 3. Curtis, E. J., Fraser, F. C., and Warburton, D.: Congenital cleft lip and palate, Amer. J. Dis. Child. 102: 853, 1961. 4. B88k, J. A.: A contribution to the genetics of congenital clubfoot, Hereditas 34: 289, 1948. 5. Carter, C. O.: The inheritance of colmnon congenital malformations, Progr. 1Vfed. Genet. 4: 59, 1965. 6. Record, R. G., and McKeown, T.: Congenital malformations of the central nervous system.

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Polygenic inheritance o[ common mal/ormations

III. Risk of malformations in slbs of malformed individuals, Brit. J. Soc. Med. 4: 217, 1950. WiUiamson, E.: Congenital malformations of the central nervous system in the Southampton area, Brit. J. Med. Genet., 1965. MacMahon, B., Pugh, T. F., and Ingalls, T. H.: Anencephalus, spina bifida and hydroeephalus. Incidence related to sex, age, race, and season of birth and incidence in siblings, Brit. J. Prey. Soc. Med. 7" 211, 1953. Record, R. G., and Edwards, J. H.: EnvironmentaI influences related to the aetiology of congenitaI hip disease, Brit. J. Prev. Soc. Med. 12: 8, 1958. Metrakos, J. D., Metrakos, K., and Baxter, H.: Clefts of the lip and palate in twins, ineluding a discordant pair whose monozygosity was confirmed by skin transplants, Plast. Reeonstr. Surg. 22: 109, 1961. Idelberger, K,: Die ErbpathoIogie der sogenannten angeborenen Huftverenkung, Munich, 1951, Urban und Schwarzenburg. McKeown, T., MacMahon, B., and Record,

13.

14. 15.

16. 17. 18.

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R. G.: Evidence of postnatal environmental influence in the etiology of infantile pyloric stenosis, Arch. Dis. Child. 27: 386, 1952. Kolah, P. J., Master, P. A., and Sanghvi, L. E.: Congenital maIformations and perinatal mortality in Bombay, Amer. J. Obstet. Gynec. 97- 400, 1967. Chung, C. S.: University of Hawaii School of Public Health, personal communication. Saldanha, P. H., Cavalcanti, A. A., and Lemos, M. L.: Incidencia de defeitos congenitos na populacao de Sao Paulo, Rev. Paul. Med. 63: 211, 1963. McKeown, T., and Record, R. G.: Seasonal incidence of congenital malformation of the central nervous system, Lancet I: 192, 1951. Edwards, J. H.: Congenital malformations of the central nervous system in Scotland, Brit. J. Prey. Soc. Med. 12: 115, 1958. Abou-Daoud, K. T.: Congenital malformations observed in 12,t46 births at the American University Hospital in Beirut J. Med. Liban. 19: 113, 1966.