Discordant abnormalities in monozygotic twins

Discordant abnormalities in monozygotic twins

64 T h e J o u r n a l of P E D I A T R I C S Discordant abnormalities in monozygotic twins Congenital abnormalities are more often seen in monozygo...

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T h e J o u r n a l of P E D I A T R I C S

Discordant abnormalities in monozygotic twins Congenital abnormalities are more often seen in monozygotic twins, especially with a monochorionic placenta, than in dizygotic twins. Although abnormalities are more frequently concordant in monozygotie than in dizygotic twins, discordance for the abnormalities among the former is strikingly frequent. Among 24 consecutive pairs of monochorionie (i.e., monozygotic) twins, five sets were discordant for various phenotypic traits. During the same period, among 79 palrJ of diehorial twins, an abnormality was noted in only one pair, and this was discordant. The twin method has not been extensively applied to the study of the relative contributions of heredity and environment in the development of congenital disease. Its use in such studies is described and the various factors which may account [or intrapair differences in isogenic individuals are discussed.

Bernard J. Fogel, M.D.,* Harold M. Nitowsky, M.D., ~ and Peter Gruenwald, M.D. '~* BALTIMORE,


T ~I E P K E N O T Y P E of Iiving organisms is a result of the interaction of genetic constitution and environment, the latter including factors acting not only after, but also at and before birth. Since the interaction be-

From the Departments of Pediatrics and Pathology, Sinai Hospital of Baltimore and the Johns Hopkins School of Medicine, Baltimore, Md. Supported in part by grants [ram the Association for the Aid of Crippled Children and the National Association [or Retarded Children and by National Institutes of Health Grant HD-00547. *Department of Pediatrics. ~*Department oJ Pathology. Address, Sinai Hospital o] Baltimore, Belvedere Avenue at Greenspring, Baltimore, Md. 21215.

tween heredity and environment is so complex, it would seem futile to attempt to make clear distinctions between the effects of these agents. Nevertheless, studies of nearly isogenie strains of experimental animals and plants and their responses to environmental alterations have been useful in assessing the relative contribution of nature and nurture in expression of the phenotype. Although isogenic strains are not available for such tests in man, and it is not possible to control at will the environment in which phenotypic characteristics develop, the occurrence of twinning provides an approach to this question. Monozygotic (MZ) twins are isogenic and permit studies of the effects of environmental variations, while dizygotic

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Discordant abnormalities in monozygotic twins

(DZ) twins are genetically different and allow studies of the effects of different genotypes in an environment which m a y be assumed to be similar. I n general, a greater intrapair correlation or a greater concordance for various phenotypic traits in M Z as compared to D Z twins has been considered to reflect the genetic identity of the former. T h e method of studying twins has not been extensively applied to the study of the interaction of heredity and environment in the development of congenital malformations. Since discordance for phenotypic traits has been observed in twins presumed to be monozygotie, 1-6 it is obvious that prenatal environmental factors play an important role in fetal development. However, zygosity has been poorly substantiated in some of these reports, and it is possible that discordance occurred in twins who were not genetically identical. T h e purpose of this report is to describe five instances of discordance in phenotypic traits present at birth in monozygotic twins, and to review the factors which might account for the development of striking intrapair differences in isogenic individuals. RESULTS

T h e five cases of discordant monozygotic twins were observed a m o n g 9,000 births over a period of approximately 24 months. During this time 103 sets of twins were born. T h e fetal membranes of all placentas were examined grossly and microscopically. Twenty-four sets of like-sexed twins were monochorionic, and 51 dichorionie. T h e remaining 28 pairs were of the opposite sex. Assuming that equal numbers of DZ twin pairs are. like-sexed and unlike-sexed, it is estimated that 46 per cent of the twins were monozygotic, and 54 per cent dizygotic (Fig.

1). T h e 5 discordant pair's were seen a m o n g the 24 consecutive pairs of monochorial, and therefore monozygotic, twins. T h e r e were no other instances of gross ma/formation, concordant or discordant, in this group. A m o n g 79 pairs of dichorionic twins, there was only one instance of discordance in a malforma-


tion (meningomyelocele) in opposite-sexed twins; all other twin pairs were normal. Discordance of birth weight exceeding 20 per cent of the weight of the larger twin was three times as frequent in monochorial as in dichorial twins; Case 5 is the most severe example encountered. All but two of the monochoriai placentas had readily recognizable vascular anastomoses in the chorion. I n fused placentas of dichorionic ( M Z or DZ) twins, a division into two portions can usually be recognized without difficulty. In contrast, the placenta of m o n o c h o r i a l twins is truly a joint rather than a fused placenta. W h e n it is examined, a separation of portions belonging to one or the other twin is difficult and arbitrary, and sometimes entirely impossible. This was true in all of the cases presented in this paper. CASE


Case 1. Twin female infants were born to a 19-year-old Caucasian primigravida in the thirty-second week of gestation. Multiple pregnancy was unsuspected although she was thought to have hydramnios. A determination of the amount of amniotic fluid was impossible because of the spontaneous rupture of one o~ the sets of membranes prior to admission. The pregnancy had been otherwise uncomplicated, and the mother was admitted to the hospital in early labor with the nnruptured set of membranes bulging. Twin A weighed 1,395 grams. She breathed and cried spontaneously. The Apgar score was 6 at one minute, and a tube was passed into the stomach without difficulty. On admission to the nursery, the baby was noted to be in moderate respiratory distress. An x-ray of the chest revealed early bronchopneumonic changes. The infant was placed in oxygen with full humidity and received penicillin and kanamycin therapy. Her condition continued to deteriorate and at 48 hours she died. Twin B weighed 1,180 grams and had primary apnea at birth. Ventilation was maintained by mouth-to-endotracheal tube respiration, and after 20 minutes the infant began to breathe irregularly by herself. A tube could not be passed into the stomach. She was transferred to the nursery, with severe respiratory distress. X-rays of the chest revealed no aeration of both lung fields although a moderate amount of air

6 6 Fogel, Nitowsky, and Gruenwald

January 1965


Monoehorial Placentae






Dieho~ial Plaeentae

Diehorial Placentae









1 }


Approximately 45>


28 . ~

.Z Twins



SgN DZ Twi~s

Total - 103

* Estimate, based on Weinbergrs rule. 5

was noted in the stomach, bulb, and proximal duodenum. The infant's condition did not improve and she died at 5 hours of age. An autopsy of Twin A showed no external abnormalities. The lungs had many red, fairly firm areas but were not completely airless. A microscopic examination revealed atelectasis and hemorrhage, with remnants of hyaline membranes. No other significant findings were present. Twin B also was externally normal. The lungs were airless and firm and, microscopically, contained hyaline membranes. There was atresia of the midportion of the esophagus; the lower portion originated at the carina as the straight continuation of the trachea and connected with the stomach. Case 2. Twin female infants were born in the thirty-sixth week of gestation to a 39-year-old Caucasian woman who had diabetes. During pregnancy, the mother received 100 units of lento insulin daily and the diabetes was difficult to regulate. The pregnancy was also complicated by hydramnios. The presence of twins was confirmed by x-ray. Twin A weighed 2,680 grams and was grossly edematous and plethoric at birth. The infant breathed and cried spontaneously, and had no obvious abnormalities. Twin B weighed 2,875 grams and was also edematous at birth. There was a large lumbar meningomyelocele with paraplegia and a sensory level at approximately the level of the second lumbar vertebra. There was also incontinence of the bowel and bladder. X-ray examination revealed a wide spina bifida starting at the third lumbar vertebra and extending to the first sacral. The head was grossly microcephatic, with a circumference of 27 cm. (Twin A: 31 era.). Chromosome studies were carried out on cells

Fig. 1.

from skin culture and revealed a normal karyotype for both infants. At 6 months of age, Twin A was doing well and developing normally. T w i n B underwent operation for closure of the meningomyelocele at 1 month of age. Postoperatively, she developed hydrocephalus. There has been no sensory or motor function below the level of the second lumbar vertebra. At the age of 6 months, the infant can hold up her head but motor development is retarded. Case 3. Male twins were delivered at 33 weeks of gestation. There was polyhydramnios estimated at 8,000 to 10,000 c.c. Twin A weighed 2,400 grams and was edematous, with a protuberant abdomen present at birth; after taking one gasp, he died. Twin B was stillborn. He weighed 595 grams and was markedly deformed. At autopsy, Twin A had edema of the head and trunk, and thin extremities. The organs showed no significant lesions, and the weights were within normal limits, except for the brain and the thymus which were somewhat small both for gestationat age and body weight. T w i n B was an acardius. There was no head, but there was a 4 by 4 by 1 cm. protrusion of the anterior aspect of the upper chest, partly covered by hair. The right upper extremity was absent, and the left greatly deformed. The anterior body wall had a 6 by 3 cm. skin defect covered by a translucent membrane, and attached to it was an umbilical cord with one artery and one vein. The anus was absent. The left lower extremity was nearly normal, the right greatly deformed. Internally, heart, lungs, liver, stomach, spleen, and pancreas were absent. T h e adrenals, kidneys, and part of the intestine were greatly hemorrhagic. There was

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Discordant abnormalities in monozygotic twins 6 7

a joint placenta with a single amniotic sac weighing 620 grams. The cords were inserted 14 cm. apart, and several vessels ran in the chorion from one to the other. Case 4. Viable male twins were born to a 26year-old Negro woman at approximately 35 weeks' gestation, after an uncomplicated pregnancy. Prior to delivery, there was a clinical suspicion of twins. Twin A weighed 2,175 grams and had an Apgar score of 10. This infant was normal, and his course in the hospital uncomplicated. Twin B was delivered by an assisted double footling breech extraction. He weighed 1,431 grams and had an Apgar score of one. The infant received mouth-to-tube resuscitation and after 10 minutes began to breathe irregularly by himself. He had moderate respiratory distress, the lungs were poorly aerated, and there were rales at both bases. Respiratory distress became progressively worse, and the infant died at 6 hours of age. Chromosome studies on cells grown from skin pnnch biopsies revealed a normal karyotype for both twins. A post mortem examination of Twin ]3 showed no striking external abnormalities except microcephaly. The viscera, liver, spleen, and kidneys had areas of scarring, with depressed portions on the surface. Microscopically, the presence of scars without remnants of the degenerated tissue was confirmed. The brain weighed 80 grams (normal weight for gestational age, 325 grams; for body weight, 200 grams). The convolutions were well developed. The gyri had a yellowish, crumpled appearance in the parasagittal portions of both parietal lobes, continuing into large portions of the temporal and occipital lobes. On section, these areas were yellowish and opaque, with many cavities in the underlying white matter. The gyri in these areas were thin and atrophic. Microscopically, there was extensive atrophy

with various stages of cavitation, gliosis, and occasional granuloma-like formations. The brain and viscera were examined for cytomegalic inclusion bodies and Toxoplasma, but none were found. Case 5. Twin female infants were born to a 39-year-old Caucasian female at 41 weeks' gestation. The pregnancy was uncomplicated. Twin A had a vertex delivery, weighed 3,090 grams, and was 48.5 cm. long. Twin B was delivered as a double footling breech, weighed 1,545 grams, and was 41 cm. long. Both infants breathed and cried spontaneously and had Apgar scores of 10. Twin A was discharged at 4 days of age and twin B at 27 days; both were in good condition. DISCUSSION M a l f o r m a t i o n s are m o r e c o m m o n in M Z than D Z twins. A l t h o u g h M Z twins are m o r e frequently c o n c o r d a n t for the abnormality than D Z twins, it is known that the f o r m e r are often discordant for the affected trait. A s u m m a r y of several reports concerning the occurrence of m a l f o r m a t i o n s in twin pairs is given in T a b l e I. T h e five pairs of M Z twins, discordant for m a l f o r m a t i o n s or phenotypic traits described in the present report, are in accord with these findings. A n analysis of twins provides a m e t h o d for the study of some of the mechanisms responsible f o r congenital anomalies. It involves a comparison of M Z and D Z twins in an a t t e m p t to obtain clues to the relative contribution of nature an d n u r t u r e in the p r o d u c t i o n of i n t r ap ai r differences? 2 T h e greater concordance in M Z as c o m p a r e d to D Z twins is generally t h o u g h t to reflect the genetic identity of the former, and attempts

T a M e I. Di s co rd an c e f r e q u e n c y for m a j o r congenital m a l f o r m a t i o n s in M Z twins


I Monozygotic 1% for discordant the twin t)airs abnormality

Clefts of lip and palate



Congenital clubfoot Esophageal atresia and tracheoesophageal fistula Malformations of the central nervous system Major malformations in Japanese infants Congenital heart disease e-Estlmated number of MZ twin pairs.

40 66 226 56 13

68 100 91 100 100

Author Metrakos, Metrakos, and Baxter 1 B55k 7 Haight s Record and McKeown 9 NeeP 0 Uchida and RowO 1

6 8 Fogel, Nitowsky, and Gruenwald

are frequently made to assign quantitative values to the contributions which heredity and environment make in determination of the observed differences. In analyzing such data, it is assumed that the environment in which two identical twins develop is on an average neither more nor less different from that of DZ twins. The average intrapair difference or discordance of a trait for MZ twins is then regarded as a measure of the effect of environmental differences. Whenever DZ twins have greater intrapair differences than MZ twins, the excess is taken as a measure of the effect of genetic differences between the former. Since antenatal and postnatal environmental influences for MZ and DZ twins may not be comparable, it would seem unwise to attribute too much significance to the absolute differences in concordance or discordance frequencies. Unfortunately, comparisons which involve abnormal traits are usually restricted to twin pairs containing one or two affected members, and so consideration of the concordance frequency of nonaffeeted pairs is usually omitted. While the study of twins affords recognition of a hereditary basis for phenotypic differences, it does no.t permit an analysis of the genotypes responsible and, thus, provides no answer to the question of whether dominant or recessive genes, autosomal or sex-linked alleles, or single or polygene combinations are responsible for the appearance of the trait under consideration. Neither does recognition of the environment as having an effect on the variability of the phenotype disclose what kinds of factors may be involved. In addition to these limitations, the method of the study of twins may be invalid if zygosity is not established correctly. Zygosity can be determined by the study of various somatic characteristics and, in some instances, by careful examination of the fetal membranes. The somatic traits, most frequently studied include detailed blood grouping, dermatoglyphic and iris patterns, eye and hair color, ear lobe form, tooth morphology, and general appearance. In regard to fetal membranes, it is generally

January 1965

conceded that monozygosity is indisputable when there is a monochorionic placenta. There are, however, reports of monochorionic and even monoamniotic dizygotic twinning resulting from fusion and secondary breakdown of adjoining fetal membranes. 13, 1~ In the fused placentas of DZ twins, anastomoses between the twins' circulatory systems are rare; this is evident from the small number of blood group chimeras. Extensive vascular anastomoses in monochorionic placentas, however, are not rare and lend additional support to. the assumption of a single ovum origin. Since about 30 per cent of identical twins have a dichorionic placenta, 15 in cases of like-sexed dichorial twins, examination of somatic characteristics or reciprocal skin grafts is necessary for the determination of zygosity. Potter 1G has stated that the zygosity of 80 per cent of twins can be established at birth if, in addition to monochorionic and unlike-sexed twins, the major blood group,s of dichorionic like-sexed pairs are determined. I n spite of the variety of characteristics tested, it may be impossible to. classify with certainty 1 to 5 per cent of like-sexed dichorial twins27 Even when zygosity has been correctly determined, and discordant abnormalities in nonisogenic individuals excluded, there: remains a sizable group of MZ twins that are discordant at birth for various phenotypic traits or congenital malformations. Various factors may account for the differences. These include genetic alterations resulting from gene mutations or chromosomal aberrations in the: cells of one of the embryos following cleavage, developmental accidents which might occur in one of the zygotes on a purely random basi% and the effects of circulatory alterations or the action of a variety of exogenous agents. Similar factors may be invoked to explain the variations in the incidence of spontaneous congenital malformations, or the variations in effects of teratogenic agents in inbred strains of animals, as well as the: asymmetry often noted in the manifestation of a defect in a single individual.

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Discordant abnormalities in monozygotic twins


While M Z twins are usually identical in genotype, genetic differences may arise by mutation after the point at which the two zygotes become separate from one another. Experimental evidence indicates that genes are susceptible to mutation in many or perhaps all cells. Thus, a single individual may be mosaic, with tissues containing normal and mutant cells. Whether a mutation is restricted to somatic cells or has occurred in germ cells as well can be determined only by studies of the transmission of the mutant allele in successive generations of individuals. Some mosaic human abnormalities are believed to result from mutation during early embryonic development. These may arise spontaneously, or perhaps as a result of environmental factors such as ionizing radiation or chemical and biologic agents. Such genetic alterations during development may affect one of a twin pair, just as they can differentially involve parts of a single embryo. T h e report of M Z twins discordant for the sex-linked disorder, hemophilia, would suggest such a spontaneous mutation during development? s Genetic changes in somatic cells can also arise by gross chromosomal aberrations, as a result o.f such alterations as deletions or mitotic nondisjunction. Prior to the description of chromosomal abnormalities in Down's syndrome, the role of genetic factors in the etiology of this disorder was supported by studies of twins? 9' 20 Down's syndrome was always concordant in M Z twins, and all were like-sexed. T h e frequency og concordance among DZ twins was the same as that expected for siblings of a single birth. These facts were consistent with the notion that the disorder had an overwhelming genetic etiology. However, the low familial incidence and the striking association with maternal age suggested the role of other factors. The demonstration of a characteristic chromosomal abnormality in patients with Down's syndrome, which has been ascribed to. meiotic nondisjunction during oogenesis, offers an adequate explanation for the high rate of concordance in MZ


twins. The recent demonstration of several MZ twin pairs discordant for Down's syndrome suggests that nondisjunction or other chromosomal aberrations may occur following fertilization also. TM 22 Several hypotheses have been offered for these observations, ineluding: 1. Mitotic nondisjunction occurring in one of the cells shortly after cleavage, with death of the daughter cell monosomic for the 21 chromosome and survival of the cell with 21 trisomy. The consequences of this process will depend upon the stage of development at which it occurs and the distribution of cell type's at the time of separation of the two embryos within the conceptus. On the one hand, an embryo with 21 trisomy and another with normal chromosomes may result; on the other, both embryo.s, may be mosaics, one containing a preponderance of normal cells and the other of cells trisomic for chromosome 21. 2. Meiotic nondisjunction resulting in a zygote with 21 trisomy. After cleavage of the embryo., however, there is loss of the additional 21 chromosome in the cells of one of the zygotes. I n addition to MZ twins discordant for mongolism, discordance for Turner's syndrome has been described in an M Z twin pair; one was a normal male with an X Y chromosome pattern and the other a phenotypic female with an X O pattern. 23 This alteration may have resulted from loss of a Y chromosome in the cells of one of the embryos after cleavage. NONGENETIC BIASES INTRINSIC TO THE CONCEPTUS

Early developmental differences. In contrast to DZ twinning, the M Z form results from an abnormal developmental process which, at one of several early stages, results in the formation of two. embryos from one zygote. Thus, proceeding from early to late occurrence of the original abnormality, the result may be dichorionic twins, monochorionic twins with 2 amnia or 1 common amnion, or conjoined twins (double monsters). In the development of monochorionic


Fogel, Nitowsky, and Gruenwald

twins, no actual division occurs; instead, 2 embryonic cell masses form inside the single trophoblastic shell, or 2 embryonic discs or 2 primitive streaks in one embryonic cell mass.

In keeping with common experience in other fields of teratology, this early abnormal developmental process m a y not be regulated to perfection and thus produces partners that are unequal from the start, or it may be followed by continued abnormal development affecting the partners equally or unequally. There are pertinent examples even among the few observed early embryonic pairs of M Z twins. One early ovum contained a normal embryo in the presomite stage, and an entirely separate, much smaller embryonic cell mass nearby, not connected with the trophoblast by a body stalk. =* In another pair described by one of us, 25 one twin in the 13 somite stage had the usual connection with the placenta. The other twin had developed in the same embryonic disc cranial to, and in tandem with, the first, but without its own direct connection with the placenta. A third twin, even though observed late in gestation, had an abnormality that must have originated in the earliest stages of embryogenesis. In this acardius, born along with a normal living infant, there was radiologic evidence of a typical, fused, sirenoid lower extremity. 2s In the first one of these 3 examples, the smaller embryo might well have disappeared without leaving a trace. In the second example, an acardius might have developed on the basis of a primarily abnormal circulation, and in the third, an acardius did develop. If the derangement of development accompanying or following the process of twinning were more subtle than in these 3 examples, discordant malformations could be more localized and affect single organs as in Cases 1 and 2 discussed previously. Considering the rapidly changing patterns of growth, and of susceptibility to injurious influences, even a slight disturbance of the synchronous development of twins, may produce a significant difference in the reaction to such influences and thus result in discord-

January 1965

ant abnormalities in genetically normal twins or modifications of the expression of abnormal hereditary traits present in both p,artners2 Late embryonic (fetal) differences. If twin embryos have progressed normally through early development and organogenesis, they may yet be subject to differential effects of their immediate environment within the uterus. Limitations of space or placental adequacy may be involved, as well as vascular anastomoses. It may be surmised that placental insufficiency during the first 3 months of gestation would be fatal within a short time, because of the excess of growth of the fetus over that of the placenta, a placenta unable to meet the full demands of an embryo in the early stages would certainly not support bare survival a month later. If, however, placental or preplacental insufficiency of the fetal supply line occurs during the third trimester of pregnancy, it may cause severe retardation of growth compatible with survival. 2., 2s Our Cases 4 and 5 are probably examples of this, but in the former, an unexplained, catastrophic event must have been involved as well, causing, the degenerative lesions which a r e attested to by scars in the brain, liver, spleen, and kidneys. Vascular anastomoses favoring flow in one direction cause the well-known "transfusion syndrome" of twins. 2~ Whether or not minor degrees of this are capable of producing chronic changes similar to placental insufficiency, without the typical manifestations of the syndrome, is unknown. While the circulatory imbalance of the transfusion syndrome occurs sufficiently late in fetal life to permit basically normal development of both partners, a much earlier onset must be postulated for the acardius. Some observations quoted above suggest that, at least in some cases, a primary developmental abnormality of one twin or of the mutual vascular connections may lead to aeardia. Whether or not a basically normal embryo with normal vascular relations to the chorion can be "taken over" by its twin to the point of becoming an acardius is not known.

Volume 66 Number 1 part 1

Discordant abnormalities in monozygotic twins

E X O G E N O U S AGENTS Several environmental factors are known to have caused dissimilar abnormalities in monozygotic twins. Although there have been a number of reports of congenital syphilis in one of a pair of twins, in most cases zygosity was not determined. Raskin, 3~ however, described a case of congenital syphilis in o.ne of apparently identicM twins. Monozygosity was diagnosed on the basis of a single placenta and the presence of indistinguishable somatic characteristics at 10 months of age. Identification of the blood groups was not helpful since both of the parents had virtually the same major types. The author speculated that the spirochetes localized in one area of the placenta or that the affected twin contracted the disease during delivery. Sporadic (nongoitrous) cretinism is a nonfamiliaI disorder due in most instances to a defect in the development of the thyroid gland. There have been several reports TM 22 of discordance of sporadic cretinism in monozygotic twins. In one cas& 1 the mother developed typical hyperthyroidism during the second month of gestation. She subsequently was delivered of one hypothyroid twin; the other was normal. In another case, ~2 the hypothyroid mother took 3 grains of thyroid hormone per day throughout her pregnancy. The most recent addition to the list of agents known to be teratogenic for humans is thalidomide. Mellin and Katzenstein ~3 have reviewed six pairs of dizygotic twins with malformations resulting from the ingestion of thalidomide early in pregnancy. Four sets had concordant phocomelia of the upper extremities, while the other two sets had discordant malformations. The geneticist who studies, the naturenurture problem in postnatal life cannot assume that monozygotic twins are necessarily identical at birth. T h e genetic alterations, developmental accidents, and intrauterine environmental factors which have been described can introduce biases that must be evaluated in any twin study. While such studies may provide a helpful method


in the appraisal of the etiologic factors of congenital disease, their validity is based on the determination of zygosity which, unfortunately, is often poorly substantiated in the literature. We would, therefore, urge that the placentas of all multiple births, be examined and accurately recorded. When zygosity cannot be determined immediately, an attempt should be made to establish the type of twinning by determination of the major blood groups. The correct establishment of zygosity will not only enhance the validity of the method of studying twins but will also allow identification of individuals who may be candidates for successful tissue transplants. SUMMARY

There were five sets of MZ twins discordant for various abnormalities among 24 consecutive pairs of monochorionic twins. There was only one pair discordant for malformations, and no concordant abnormalities among 79 pairs of diehorial twins were: observed during the same period. This suggests that malformations are more common in monozygotic than in dizygotic twins and that when present they are frequently discordant. Genetic alterations resulting from gene mutations or chromosomal rearrangements in the embryos following cleavage, developmental accidents occurring during the formation of the twin embryos, intrauterine environmental influences, and the action of a variety of exogenous agents are all possible mechanisms in the production of intrapair differences between presumed isogenic individuals.


I. Metrakos, J. D., Metrakos, K., and Baxter, H.: Clefts of the lips and palate in twins, Plast. & Reconstruct. Surg. 29: 109, t958. 2. Kindred, J. E.: Twin pregnancies with one twin blighted, Am. J. Obst. & Gynec. 48: 642, 1944. 3. Morison, J. E.: Congenital malformations in one of monozygotie twins, Arch. Dis. Child, hood 24: 214, 1949. 4. Maeklin, M. T.: Heredity as the cause of

7 2 Fogel, Nitowsky, and Gruenwald



7. 8.

9. 10. 11. 12. 13. 14. 15. 16. 17.

18. 19.

congenital malformations, Am. J. Obst. & Gynec. 32: 259, 1936. Price, B.: Primary biases in twin studies. A review of prenatal and natal differenceproducing factors in monozygotic twin pairs, Am. J. Human Genet. 2: 293, 1950. Gruenwald, P., and Mayberger, H. W.: Differences in abnormal development of monozygotic twins, A. M. A. Arch. Path. 20: 685, 1960. B6/Sk, J. A.: A contribution to the genetics of congenital clubfoot, Hereditas 34: 289, 1948. Haight, C.: Some observations on esophageal atresia and traeheoesophageal fistulas of congenital origin, J. Thoracic Surg. 34: 141, 1957. Record, R. G., and McKeown, T.: Congenital malformations of the central nervous system, Ann. Eugenics 15: 285, 1951. NeeI, J. V.: Study of major congenital defects in Japanese infants, Am. J. Human Genet. 10: 398, 1958. Uchida, I. A., and Rowe, R. D.: Discordant heart abnormalities in twins, Am. J. Human Genet. 9: 133, 1957. Stern, C.: Principles of human genetics, ed. 2, San Francisco and London, 1960, Freeman & Co., p. 530. Arey, L. 13.: Chorionic fusion and augmented twinning in the human tube, Anat. Rec. 23: 253, 1922. Lawler, S. D.: Mongolism in one of twins, Brit. M. J. 2: 1172, 1950. Benirschke, K.: Accurate recording of twin placentation, Obst. & Gynec. 18: 334, 1961. Potter, E. L.: Twin zygosity and placental form in relation to the outcome of pregnancy, Am. J. Obst. & Gynec. 87: 566, 1963. Sutton, H. E., Vandenberg, S. G., and Clark, P.: The hereditary abilities study: Selection of twins, diagnosis of zygosity and program of measurements, Am. J. Human Genet. 14: 52, 1962. Quick, A. J., and Conway, J. P.: Hemophilia in twins, Am. J. Med. 7: 841, 1949. Friedman, A.: Mongolism in twins. Its bearing upon the question of the etiology of mongolism, A. M. A. Am. J. Dis. Child. 90: 43, 1955.

January 1965

20. Allen, G., and Baroff, G. S.: Mongoloid twins and their siblings, Acta genet, reed. et gemel. 5: 294, 1955. 21. deWolff, E., Sch~irer, K., and Lejeune, J.: Contribution ~ l'ttude des jumeaux mongoliens. Un cas de monozygotisme hdt~rcaryote, Helvet. paediat, acta 17: 30i, I962. 22. Fanconi, V. G.: Weitere F~ille yon wahrscheinlich eineiigen Zwillingen, yon denen der eine gesund ist, der andere einen Mongolismus zeight, tIelvet, paediat, acta 17: 490, 1962. 23. Turpin, R., Lejeune, J., Lafoureade, J., Chigot, P. L., and Salmon~ C.: Presomption de monozygotisme en dfipit d'un dimorph{sme sexuel: sujet masculin XY at sniet neutre haplo X, Compt. rend. Acad. sc. 252: 294.5, 1961. 24. Streeter, G. L.: A human embryo (Mateer) of the presomite period, Contrib. Embryol. 9: 389, 1920. 25. Gruenwatd, P.: Early human twins with peculiar relations to each other and the chorion, Anat. Rec. 83: 267, 1942. 26. Kappelman, M.: Acardius amorphus, Am. J. Obst. & Gynee. 47: 412, 1944. 27. Gruenwald, P.: Chronic fetM distress and placental insufficiency, Biol. Neonat. 5" 215, 1963. 28. Babson, S. G., Kangas, J., Young, N., and Bramhall, J. L.: Growth and development of twins of dissimilar size at birth, Pediatrics 33" 327, 1964. 29. Bernirschke, K.: Twin placenta in perinatal mortality, New York J. Med. 61: 1499, 1961. 30. Raskin, R. A.: Congenital syphilis in one of apparently identical twins, Am. J. Syph. 35: 334, t951. 31. Von Harnack, G. A.: Eineiige Zwillinge mlt diskordanter Hypothyreose, Arch. Kinde:h. 146: 60, 1953. 32. Warkany, J., and Selkirk, T. K.: Discordant monozygotic twins; Hypothyroidism, A. M. A. Am. J. Dis. Child. 89: 144, 1955. 33. Mellin, G. W., and Katzenstein, M.: The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies, New England J. Med. 267: 124t, 1962.