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Chromosome Abnormalities and Intrauterine Growth Retardation
Chromosome Abnormalities and Intrauterine Growth Retardation LEONARD E. REISMAN, M.D.*
Falkner has stated that some of the most tantalizing, frustrating, and needed areas of study are found in human development in utero. s He cited the difficulties in obtaining representative sampling of healthy fetuses, in obtaining standards for antenatal growth, and in measuring gestational age precisely. Valid studies of normal intrauterine growth are indeed rare. 30 This volume is devoted basically to the problems of fetuses that grow at a slower rate than normal and which then are disproportionately small for their gestational ages. Elsewhere, the factors which interfere with normal fetal growth will be approached from biochemical, infectious, endocrine, nutritional and iatrogenic viewpoints (as well as others). This brief article will be confined to the relationship between specific disorders involving chromosomal aberrations and intrauterine growth retardation.
OTHER SPECIES Growth and developmental failure on a chromosomal basis has been described in reports on other species. Most of these reports have antedated the relatively recent recognition of the chromosomal abnormalities in man. Plants,! some varieties of amphibia,9 and, of course, Drosophila,6 with numerically or structurally abnormal chromosome constitutions, have been reported to show defects in growth along with other anomalies. The monosomic (haplo-4) Drosophila melanogaster, which lacks the very small fourth chromosome, characteristically is smaller and weaker, and is retarded in development, in comparison with the normal fly.6 The loss of corresponding amounts of genetic material from any of the fly's other three larger autosomal chromosomes, and from the X chromosomes, has a similarly deleterious, and often very drastic, effect.
*Associate
Professor of Pediatrics, Associate Professor of Pathology, Jefferson Medical College; Hematologist to the Clinical Laboratories, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
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On the other hand, the Drosophila that is trisomic for the X chromosome (the triplo-X or superfemale) is a small, sterile, somewhat tatteredappearing fly that is destined to be a victim of premature death-which frequently occurs even before emergence. Trisomic and monosomic mutants of the datura plant species (known as the Jimson weed or thornapple) also demonstrate marked deficiencies in growth. 1 Many of the trisomic Datura variants do not survive without special care in a greenhouse. Parallels in lower animals and vertebrates apparently are rare, but certainly no comparable search for chromosome anomalies in them has been made. Intrauterine (and postpartum) growth retardation, however, is a common denominator in many of the clinical syndromes associated with the cytogenetic abnormalities that have been described in man over the past decade.
DOWN'S SYNDROME Infants with Down's syndrome have a lower birth weight and are shorter than normal babies. Some early studies based on relatively small numbers of infants found the mean birth weight of children with Down's syndrome to be within normal limits or only slightly below normal.2 9 A number of investigators, however, have clearly shown that the mean birth weight difference between mongoloid and normal infants is as much as a pound or so at the same level of maturity.3, 12, 13,20 Hall found the mean weight at birth to be 400 gm. lower in children with Down's syndrome;13 Gustavson noted even more marked differences in males compared to females. 12 Normal male infants outweighed their mongoloid counterparts by 650 gm., but the difference between mongoloid and normal females was only 380 gm. Smith and McKeown's constantly quoted work showed a mean birth weight in Down's syndrome of 6.38 pounds as compared to 7.10 pounds in normal newborns at all gestational periods. 26 The difference moved closer to one-half pound at 38 to 40 weeks of gestation. These authors also found that twice as many mongoloid infants had birth weights under 6 pounds in comparison with normal babies. Fifty per cent of the newborns with Down's syndrome were under 6 pounds in weight. Furthermore, as many as 40 per cent of infants with Down's syndrome are admitted to a premature nursery. In these studies, as well as in most reports, the birth weights of children with Down's syndrome show a 10 or 15 per cent decrease from the normal average. Comparison of the newborn with Down's syndrome with normals indicates that the former, measuring between 18 and 20 inches (46 to 51 cm.) in length, is slightly shorter than the average normal infant,21 That is, the mongoloid infant has a mean length of 2 or 3 cm. less than the normal baby. The growth rate in Down's syndrome, of course, continues to lag after birth. Growth retardation manifests itself primarily in shortness of stature and, often, as low weight (Fig. 1). Skeletal maturation may be normal (or even advanced) at birth, as indicated by the fact that one third of mongoloid infants have one or more centers of ossifica-
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Figure 1.1. Intrauterine Intrauterine and and postnatal postnatal Figure growth retardation retardation in in Down's Down's syndrome syndrome isis growth demonstrated by by these these two two sets sets of of twins. twins.A, A, demonstrated Male twin twin with with Down's Down's syndrome syndrome (right) (right) Male had birth birth weight weight 11 pound pound less less than than his his had sister. B, B, At At 99 years years of of age, age, stunting stunting in in sister. Down's syndrome syndrome child child is is obvious. obvious. (A (A is is Down's from Reisman, Reisman, L. L. E., E., and and Matheny, Matheny, A. A. P. P.,, from Jr.: Genetics Genetics and and Counseling Counseling in in Medical Medical Jr.: Practice. St. St. Louis, Louis, C. C. V. v. Mosby Mosby Co., Co., 1969.) 1969.) Practice.
tion in the wriSt. 13 Benda described a "hypomorphy" in bone growth, involving the long bones but more pronounced in the hands, fingers, feet, and toes, which leads to a generalized shortening and disproportionate growth at birth. 3 When we consider that the birth weight of Down's syndrome infants is significantly lower than that of normal infants, we must remember that the length of gestation is shorter. Smith and McKeown found an average gestational period 10 days shorter among the mongoloid babies (270 days as compared to 280 days in the normal population).26 The consensus of most workers is that the duration of pregnancy is 7 to 10 days less for infants with mongolism than normal infants. Again, there is a difference between males and females: the newborn males with Down's syndrome have shorter gestational periods than females. 12 These same workers also conclude that the decreased birth weight in Down's syndrome cannot be attributed solely to the shortened gestational period. The early onset of labor (at 38 weeks or so rather than 40) clearly could not explain the marked differences in birth weight that have been described previously. The birth weights in Down's syndrome are disproportionately decreased even if we take into account the shortened fetal periods. 26 Unfortunately, the assumption that there has been a reduced fetal growth rate and that there has been a retardation of embryological development have not been ably documented (primarily because the problems stated in the opening paragraph of this paper relate also to abnormal fetuses). It is fair to state that the trisomy of the G group chromosome in Down's syndrome does interfere somehow with the usual
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growth rate, and apparently the intrauterine growth failure is unrelated causally to an environmental problem. The finding of normal placental weights and the lack of morphological abnormalities of the placenta in mongolism also point to growth failure as being an intrinsic phenomenon of the trisomic fetus rather than a problem of placental insufficiency.26 The origin of fetal growth arrest is as speculative in nature as is the origin of the other congenital malformations in Down's syndrome. The increased risk of leukemia, "mongoloid facies," and mental retardation, as well as stunting, might be attributed to the duplication of certain gene loci on the G group chromosome. What does appear likely is that the trisomic complement and its genetic imbalance disturb the development of the fetus by causing a generalized embryologic chaos. II. 28
18 TRISOMY The low birth weight of the puny, malformed infant with trisomy 18 needs no extensive documentation. 31 Weeks prior to the baby's delivery, the obstetrician and the mother may have had suspicions about the baby's being small because of the mother's small gestational weight gain and the observed feeble fetal movements. One series of 90 infants with 18 trisomy reported by Warkany had an average birth weight of 2183 gm. (4 pounds, 13 ounces).33 Half of the gestational periods that were reported were over 40 weeks, the other half being 38 to 40 weeks. Polani reported a mean weight for these infants of 2333 gm. at birth, with an average gestational period of 40.4 weeks. 22 Considering these reports, one finds both prematurity and postmaturity in terms of the length of the gestational period, but, conversely, consistent growth retardation in utero. Utilizing a weight/gestational age analysis, the majority of birth weights in 18 trisomy fall below the tenth percentile for a given gestational age. 25 The placenta in 18 trisomy has been noted to be "small" by some observers,27 but the data remain too scanty to draw any conclusions about the relationship between placental size and intrauterine growth retardation. In addition to the diminution in size, there have been several reports of pathologic changes, such as areas of patchy fibrosis and focal placental infarctions. 14 The presence of only one umbilical artery is also frequently noted. However, relatively little is known yet concerning the anatomy, let alone the function, of human placentas with any of the chromosome abnormalities. No consistent anatomic malformations or malfunctions of such placentas have been described. Certainly, there might be more subtle biochemical or physiological phenomena which do cause degrees of placental insufficiency.
D} TRISOMY The prenatal growth in DI trisomy is less altered than in 18 trisomy, but a majority of newborns with DI trisomy do have smaller than expected birth weights. Thirty cases analyzed by Warkany according to birth weight/gestation time had an average birth weight of 2480 gm.
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(5 pounds, 7112 ounces).33 Most of the infants were born at 38 to 4.0 weeks of gestation. Polani's review showed a mean fetal weight in the Dl trisomy syndrome of 2485 gm., with an average gestation of 38.4 weeks. 22 As is found among children with Down's syndrome, there is no association between intrauterine growth retardation and congenital malformations. The birth defects related to this syndrome are distributed throughout the entire weight range. The unreliability inherent in predicting phenotypic expression of chromosomal mosaicism is true of intrauterine growth as well as of other traits. One would expect a modifying effect on the various somatic defects in individuals with a mosaic complement. Pfeiffer did find a small group of infants with normal-D1 trisomy mosaicism to have a significantly higher mean birth weight than another group of full-term infants with "regular" Dl trisomy.23 Yet there is no consistent relationship between birth weight and "dosage" of cytogenetic abnormality. In Down's syndrome, there generally has been no significant difference found between the birth weights of trisomy 21 infants and trisomy 21-normal mosaics.
THE AUTOSOMAL DELETION SYNDROMES Among newborns with chromosomal deletion syndromes, intrauterine growth is impaired generally, although there is great variability. As mentioned before, the impaired fetal growth in the individual with a loss of genetic material is most likely an intrinsic defect of the developing embryo. Evidence for an abnormal placenta or a nutritional problem is lacking, as pointed out for the autosomal trisomy syndromes.
Figure 2. An example of the low birth weight for term baby is this infant with "antimongolism," partial monosomy of a G group chromosome. Birth weight at term was 4 pounds, 7 ounces. The flexed extremities held off the mattress and the well-equipped chest are consistent with a term baby, rather than a premature infant. (From Reisman, L. E., et al.: Antimongolism. Studies in an infant with a partial monosomy of the 21 chromosome. Lancet, 1 :394, 1966.)
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Seventy per cent of infants with the cri du chat (crying cat) syndrome - for which there is a deletion of part of the short arms of chromosome 5-have birth weights below the tenth percentile. Gestational periods, on the other hand, most often are within the normal range. Many case reports do not discuss birth weight, let alone give an estimate of gestational age, of newborns with the various chromosomal abnormalities. The pattern of low birth weight, accompanied by postnatal growth retardation, however, is highlighted in the recognized syndromes as well as in the more exotic structural chromosome aberrations. Thus, in "antimongolism," in other partial or total deletions of a G group chromosome, in the short-arm 18 deletion syndrome, and in the "ring chromosome" anomalies, intrauterine growth retardation is a common, if not always constant, finding (Fig. 2). Migeon was reminded of the "minute" deletions in Drosophila which, although present on the various autosomes and the X chromosome, cause phenotypically similar aberrations in the affected flies. 16 Decreased body size and developmental retardation are among the anomalies. In man, gene loci requisite for protein synthesis may be scattered on different chromosomal deletions and lead to common phenotypic aberrations. THE SEX CHROMOSOME ABNORMALITIES The baby with the Turner (45/XO) syndrome often is very small for gestational age. One third of these newborns are under 2500 gm. at birth. Short stature almost invariably is present in the child and adult with this abnormality.lo. 31 The 45/XO female generally is below the third percentile in height and only in exceptional cases will achieve a height of 5 feet. (Prenatal and postnatal growth retardation are associated also with the "male Turner's syndrome" or Noonan's syndrome, which probably represents a genetic disorder rather than a gross chromosomal error.) The deficiency of the X chromosome in Turner's syndrome results in the faulty gonadal anlage and the somatic findings which include dwarfism. As shown for the autosomal chromosome abnormalities, prenatal growth retardation and other malformations found in Turner's syndrome have been attributed to the chromosome imbalance. Certainly, the presence of nonspecific congenital heart disease, and short stature, would support this view. The evidence suggests, however, that, although the long arm of the X chromosome is necessary for normal ovarian development, it is less crucial for normal stature and prevention of the other somatic malformations.2.17.18 The few patients with the short arm of the X chromosome intact, such as those with a short arm X isochromosome, have been reported to have normal heights and few somatic anomalies. They still have defective ovaries. On the other hand, the more common isochromosome abnormality with retention of both long arms of the X - and loss of the short arms -leads to the dwarfism and the other typical stigmata of Turner's syndrome. 24
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Thus, loss of the short arm of the X appears related directly to the intrauterine and postnatal stunting. Information involving linear growth (as well as to the Xga blood group and color vision factors, for example) probably resides on the short arm of the X chromosome. Comparable genetic information must be at homologous loci on the Y chromosome, since it seems that double doses of these genes are needed for normal prenatal and postpartum development. One or, as is more likely, more genes on the X and Y chromosomes probably deal specifically with growth. The 47/XYY and 48/XXYY males would have three and four doses respectively of the homologous genetic factors, at least at an early stage of embryonic development. This might explain the excessive height of these individuals. A quantitative relationship of normal X chromosome to somatic anomalies is indicated also by the finding that many XO/XX and XO/XX/ xxx mosaic individuals have normal growth and relatively few defects, but retain the "streak" ovaries of Turner's syndrome. IS The modifying effect of chromosomal mosaicism on intrauterine growth and the various congenital anomalies that were suggested previously in the autosomal trisomy syndromes are more obvious in the Turner abnormality.
THE POLY-X SYNDROMES Unlike her Drosophila melanogaster counterpart, the human triple-X female generally does not have imy growth retardation or other clinically recognizable somatic abnormalities. The same is true of the few XXXX and XXXXX females who have been reported. It should be pointed out, however, that profound mental retardation may be present. The Lyon hypothesis might explain the relatively minor effects of the extra X chromosomes. The genetic inactivation associated with heterochromatinization of the X chromosome may render these abnormalities less deleterious to the developing embryo than those errors involving autosomes. Individuals with Klinefelter's syndrome (47/XXY) reveal no physical stigmata at birth or prenatally. The XXXXY males often do have a severe degree of growth retardation, but intrauterine growth failure and, consequently, short stature are not consistent findings among persons with this abnormality.
DISORDERS WITH CHROMOSOME BREAKAGE Patients with Fanconi's anemia and those with Bloom's syndrome (an unusual dermatologic disorder) have several findings in common. They have low birth weights for their gestational ages, stunting of growth, varied congenital anomalies (more marked in the Fanconi anomaly), and a striking susceptibility to leukemia. Cytogenetic studies of lymphocytes, bone marrow cells, and fibroblasts derived from the skin of affected persons with both diseases are similar. There is no abnormality of chromosome number, but instead there are chromosome breaks and structural rearrangements. These structural anomalies,
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although not specific to these disorders, have become pathognomonic findings in both Bloom's syndrome and Fanconi's anemia. It is possible that the intrauterine growth retardation and dwarfing, along with the other birth defects, and the susceptibility to both chromosome breakage and leukemia, are some of the effects of the mutant pleiotropic genes. It seems more exciting to speculate that the developmental errors in the fetuses with the Fanconi and Bloom syndromes are due to the lethal effect of the damaged chromosomes on the cells of the early embryos.15 The generalized cellular dysplasia might lead on the one hand to defects in cell and tissue growth and metabolism, and on the other hand to malignant transformation.
GENERAL COMMENTS It is clear that intrauterine growth retardation, as well as postnatal stunting, are prominent features among almost all of the syndromes involving autosomal chromosome aberrations and among the XO and XXXXY sex chromosome disorders. Although it is possibly more severe in the 18 and DI trisomy syndromes, fetal growth arrest is consistently associated with all of the commonly recognized chromosomal syndromes and with the more unique structural abnormalities. But, although one has a little more insight into the background of some infants with low :1irth weight for gestational age, the explanations for the growth failure remain conjectural. Since growth after birth is subject to a host of interacting factors, it is not unreasonable to suggest that the prenatal growth of infants (both normal and with chromosomal abnormalities) is also dependent upon various factors. The significance of genetic factors in intrauterine growth, including the individual's own background, has not been discussed. Mentally retarded children without chromosome abnormalities have a significant, if not as marked, degree of growth retardation. 19 Such determinants are important factors, even in those fetuses with chromosomal aberrations. The final height of an individual with Down's syndrome, while markedly deficient, does show a relationship with parental heights, a demonstration that these genetic factors remain operative. It is obvious also that the prenatal growth retardation associated with chromosomal abnormalities is part of a continuum of events affecting the fetus. The failure of orderly mechanisms of cellular division leads to a failure of orderly development of the embryo. The deletion or inactivation of gene loci generally involving protein synthesis, or of specific genes relating to stature, or a nonspecific imbalance due to superfluous or deficient amounts of genetic material, may lead to the abnormal embryologic phenomena. The continuum of growth failure in the abnormal fetus is characterized initially by early embryonic wastage. Evidence for the lethality of the chromosomal genetic imbalance is the finding in spontaneous abortions, which have 20 per cent abnormal karyotypes. In one of Carr's early studies, he reported that chromosome abnormalities were found in early specimens of aborted offspring. 7 In all cases, the embryo (if
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recognizable) lagged in development behind that expected from the estimated gestational period. An asynchromy in development of limb buds and other organs was noted also. The incidence of such anomalies is roughly 1 :250 at birth. It is estimated that 90 per cent of abnormal conceptuses are eliminated as abortuses; the remainder survive as abnormal infants. The impaired viability and development of the abnormal fetuses after birth are related to the early deaths in the perinatal period and to the shortened survival periods almost universally found. There is also an increased incidence of stillbirths and neonatal deaths associated with intrauterine growth retardation which is recognizable but shows no chromosome alteration. 5 ,32 The growth potential of surviving individuals is also affected by hereditary intrauterine growth retardation. The chance of survival in 18 trisomy is 70 per cent to 1 month, 10 per cent to 1 year, and 1 per cent to 10 years. 34 Thus, the surviving individuals with intrauterine growth retardation only represent a small proportion of the original abnormal zygotes.
SUMMARY Intrauterine growth retardation is almost a sine qua non of the recognized chromosome abnormalities, with the exception of the poly-X and Klinefelter's syndromes. Growth arrest is most accentuated in the 18 and Dl trisomy syndromes, but it is still a significant finding in most of the other aberrations, including Down's syndrome and Turner's syndrome. The mechanisms for growth arrest in the chromosomal anomalies remain speculative, but it is clear that growth retardation in utero is a continuum of the intrinsic fetal failure of development which leads to abortions, stillbirths, early neonatal and perinatal death, and, for the survivors, a failure to thrive, markedly diminished lifespans, and, during life, inability to live normally.
REFERENCES 1. Avery, A., Satina, S., and Rietsema, J.: Blakeslee: The Genus Datura. New York, The Ronald Press, 1959. 2. Barr, M. L.: The sex chromosomes in evolution and in medicine. Canad. Med. Assoc. J., 95:1137,1966. 3. Benda, C. E.: The Child with Mongolism. New York, Grune & Stratton, 1960. 4. Bloom, G. E., Warner, S., Gerald, P. S., and Diamond, L. K.: Chromosome abnormalities in constitutional aplastic anemia. New Eng. J. Med., 276:8, 1966. 5. Brent, R L., and Jensh, R P.: Intra·uterine growth retardation. In Woollam, D. H. M., ed.: Advances in Teratology. London, Logos Press, 1967. 6. Bridges, C.: Nondisjunction as proof of the chromosome theory of heredity. Genetics, 1: I, 1916. 7. Carr, D. H.: Chromosome studies in abortuses and stillborn infants. Lancet, 2:603,1963. 8. Falkner, F.: General considerations in human development. In Falkner, F., ed.: Human Development. Philadelphia, W. B. Saunders Co., 1966. 9. Fankhauser, G., and Humphrey, R R: The origin of spontaneous heteroploids in the progeny of diploid, triploid, and tetraploid axolotl females. J. Exp. Zool., 142:379,1959. 10. Federman, D. J.: Abnormal Sexual Development. Philadelphia, W. B. Saunders Co., 1967. 11. Ford, C. E.: Chromosomal abnormality and congenital malformation. In Ciba Foundation Symposium on Congenital Malformations. London, J & A. Churchill, 1960. 12. Gustavson, K. H.: Down's Syndrome: A Clinical and Cytogenetical Investigation. Uppsala, Almquist & Wiksell, 1964.
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13. Hall, B.: Mongolism in newborns. Acta. Paed., suppL 1, 1964, p. 154. 14. Hecht, F.: The placenta in trisomy 18 syndrome. Obstet. Gynec., 22:147,1963. 15. Hirschhorn, K.: Cytogenetic alterations in leukemia. In Perspectives in Leukemia. New York, Grune & Stratton, 1968. 16. Migeon, B. R.: Short arm deletions in group E and chromosomal "deletion" syndromes. J. Pediat., 69:432, 1966. 17. Moore, K. L.: Sex chromatin and gonadal dysgenesis. In Moore, K. L., ed.: The Sex Chromatin. Philadelphia, W. B. Saunders Co., 1966. 18. Morishima, A., and Grumbach, M. M.: The interrelationship of sex chromosome constitution and phenotype in the syndrome of gonadal dysgenesis and its variants. Ann. N.Y. Acad. Sci., 155:695,1968. 19. Mosier, H. D., Jr., Grossman, H. J., and Dingman, H. F.: Physical growth in mental defectives. A study in an institutionalized population. Pediatrics (SuppL), 36:465, 1965. 20. Oster, J.: Mongolism: A clinic genealogical investigation comprising 526 mongols living on Seeland and neighboring islands in Denmark. Copenhagen, Danish Science Press, 1953. 21. Penrose, L. S., and Smith, G. F.: Down's Anomaly. London, J. & A. Churchill, 1966. 22. Polani, P. E.: Chromosome anomalies. Ann. Rev. Med., 15:93, 1964. 23. Pfeiffer, R. A.: Inborn autosomal disorders: The phenotype of autosomal aberrations. In Proceedings of the Third International Congress of Human Genetics. Baltimore, Johns Hopkins Press, 1967. 24. Reisman, L. E., and Matheny, A. P., Jr.: Genetics and Counseling in Medical Practice. St. Louis, C. V. Mosby, 1969. 25. Schutt, W.: Foetal factors in intrauterine growth retardation. In MacGregor, W. G., ed.: Gestational Age, Size and Maturity. London, National Spastics SOCiety and Heinemann Medical Books, 1966. 26. Smith, A., and McKeown, T.: Prenatal growth of mongoloid defectives. Arch. Dis. Child., 30:257, 1955. 27. Smith, D. W., Patau, K., Therman, E., and Inharn, S. L.: The no. 18 trisomy syndrome. J. Pediat., 60:513, 1962. 28. Smithells, R. W.: Chromosomes and the clinician. In Hamerton, J. L., ed.: Chromosomes in Medicine. London, National Spastics Society and Heinemann Medical Books, 1962. 29. Southwick, W. E.: Time and stage in development at which factors operate to produce mongolism. Amer. J. Dis. Child., 57:68, 1939. 30. Usher, R., and McLean, F.: Intrauterine growth oflive-born caucasian infants at sea level: Standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J. Pediat., 74:901, 1969. 31. Valentine, G. H.: The Chromosome Disorders. An Introduction for Clinicians. London, Heinemann Medical Books, 1966. 32. Warkany, J., Monroe, B. B., and Sutherland, B. S.: Intrauterine growth retardation. Amer. J. Dis. Child., 102:249, 1961. 33. Warkany, J., Passarge, E., and Smith, L. B.: Congenital malformations in autosomal trisomy syndromes. Amer. J. Dis. Child., 112:502, 1966. 34. Weber, W. W., Manunes, P., Day, R., and Miller, P.: Trisomy 17-18 (E): Studies on longterm survival with report of two autopsied cases. Pediatrics, 34:533, 1964. Jefferson Medical College Philadelphia, Pennsylvania 19107
Falkner has stated that some of the most tantalizing, frustrating, and needed areas of study are found in human development in utero. s He cited the difficulties in obtaining representative sampling of healthy fetuses, in obtaining standards for antenatal growth, and in measuring gestational age precisely. Valid studies of normal intrauterine growth are indeed rare. 30 This volume is devoted basically to the problems of fetuses that grow at a slower rate than normal and which then are disproportionately small for their gestational ages. Elsewhere, the factors which interfere with normal fetal growth will be approached from biochemical, infectious, endocrine, nutritional and iatrogenic viewpoints (as well as others). This brief article will be confined to the relationship between specific disorders involving chromosomal aberrations and intrauterine growth retardation.
OTHER SPECIES Growth and developmental failure on a chromosomal basis has been described in reports on other species. Most of these reports have antedated the relatively recent recognition of the chromosomal abnormalities in man. Plants,! some varieties of amphibia,9 and, of course, Drosophila,6 with numerically or structurally abnormal chromosome constitutions, have been reported to show defects in growth along with other anomalies. The monosomic (haplo-4) Drosophila melanogaster, which lacks the very small fourth chromosome, characteristically is smaller and weaker, and is retarded in development, in comparison with the normal fly.6 The loss of corresponding amounts of genetic material from any of the fly's other three larger autosomal chromosomes, and from the X chromosomes, has a similarly deleterious, and often very drastic, effect.
*Associate
Professor of Pediatrics, Associate Professor of Pathology, Jefferson Medical College; Hematologist to the Clinical Laboratories, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
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On the other hand, the Drosophila that is trisomic for the X chromosome (the triplo-X or superfemale) is a small, sterile, somewhat tatteredappearing fly that is destined to be a victim of premature death-which frequently occurs even before emergence. Trisomic and monosomic mutants of the datura plant species (known as the Jimson weed or thornapple) also demonstrate marked deficiencies in growth. 1 Many of the trisomic Datura variants do not survive without special care in a greenhouse. Parallels in lower animals and vertebrates apparently are rare, but certainly no comparable search for chromosome anomalies in them has been made. Intrauterine (and postpartum) growth retardation, however, is a common denominator in many of the clinical syndromes associated with the cytogenetic abnormalities that have been described in man over the past decade.
DOWN'S SYNDROME Infants with Down's syndrome have a lower birth weight and are shorter than normal babies. Some early studies based on relatively small numbers of infants found the mean birth weight of children with Down's syndrome to be within normal limits or only slightly below normal.2 9 A number of investigators, however, have clearly shown that the mean birth weight difference between mongoloid and normal infants is as much as a pound or so at the same level of maturity.3, 12, 13,20 Hall found the mean weight at birth to be 400 gm. lower in children with Down's syndrome;13 Gustavson noted even more marked differences in males compared to females. 12 Normal male infants outweighed their mongoloid counterparts by 650 gm., but the difference between mongoloid and normal females was only 380 gm. Smith and McKeown's constantly quoted work showed a mean birth weight in Down's syndrome of 6.38 pounds as compared to 7.10 pounds in normal newborns at all gestational periods. 26 The difference moved closer to one-half pound at 38 to 40 weeks of gestation. These authors also found that twice as many mongoloid infants had birth weights under 6 pounds in comparison with normal babies. Fifty per cent of the newborns with Down's syndrome were under 6 pounds in weight. Furthermore, as many as 40 per cent of infants with Down's syndrome are admitted to a premature nursery. In these studies, as well as in most reports, the birth weights of children with Down's syndrome show a 10 or 15 per cent decrease from the normal average. Comparison of the newborn with Down's syndrome with normals indicates that the former, measuring between 18 and 20 inches (46 to 51 cm.) in length, is slightly shorter than the average normal infant,21 That is, the mongoloid infant has a mean length of 2 or 3 cm. less than the normal baby. The growth rate in Down's syndrome, of course, continues to lag after birth. Growth retardation manifests itself primarily in shortness of stature and, often, as low weight (Fig. 1). Skeletal maturation may be normal (or even advanced) at birth, as indicated by the fact that one third of mongoloid infants have one or more centers of ossifica-
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Figure 1.1. Intrauterine Intrauterine and and postnatal postnatal Figure growth retardation retardation in in Down's Down's syndrome syndrome isis growth demonstrated by by these these two two sets sets of of twins. twins.A, A, demonstrated Male twin twin with with Down's Down's syndrome syndrome (right) (right) Male had birth birth weight weight 11 pound pound less less than than his his had sister. B, B, At At 99 years years of of age, age, stunting stunting in in sister. Down's syndrome syndrome child child is is obvious. obvious. (A (A is is Down's from Reisman, Reisman, L. L. E., E., and and Matheny, Matheny, A. A. P. P.,, from Jr.: Genetics Genetics and and Counseling Counseling in in Medical Medical Jr.: Practice. St. St. Louis, Louis, C. C. V. v. Mosby Mosby Co., Co., 1969.) 1969.) Practice.
tion in the wriSt. 13 Benda described a "hypomorphy" in bone growth, involving the long bones but more pronounced in the hands, fingers, feet, and toes, which leads to a generalized shortening and disproportionate growth at birth. 3 When we consider that the birth weight of Down's syndrome infants is significantly lower than that of normal infants, we must remember that the length of gestation is shorter. Smith and McKeown found an average gestational period 10 days shorter among the mongoloid babies (270 days as compared to 280 days in the normal population).26 The consensus of most workers is that the duration of pregnancy is 7 to 10 days less for infants with mongolism than normal infants. Again, there is a difference between males and females: the newborn males with Down's syndrome have shorter gestational periods than females. 12 These same workers also conclude that the decreased birth weight in Down's syndrome cannot be attributed solely to the shortened gestational period. The early onset of labor (at 38 weeks or so rather than 40) clearly could not explain the marked differences in birth weight that have been described previously. The birth weights in Down's syndrome are disproportionately decreased even if we take into account the shortened fetal periods. 26 Unfortunately, the assumption that there has been a reduced fetal growth rate and that there has been a retardation of embryological development have not been ably documented (primarily because the problems stated in the opening paragraph of this paper relate also to abnormal fetuses). It is fair to state that the trisomy of the G group chromosome in Down's syndrome does interfere somehow with the usual
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growth rate, and apparently the intrauterine growth failure is unrelated causally to an environmental problem. The finding of normal placental weights and the lack of morphological abnormalities of the placenta in mongolism also point to growth failure as being an intrinsic phenomenon of the trisomic fetus rather than a problem of placental insufficiency.26 The origin of fetal growth arrest is as speculative in nature as is the origin of the other congenital malformations in Down's syndrome. The increased risk of leukemia, "mongoloid facies," and mental retardation, as well as stunting, might be attributed to the duplication of certain gene loci on the G group chromosome. What does appear likely is that the trisomic complement and its genetic imbalance disturb the development of the fetus by causing a generalized embryologic chaos. II. 28
18 TRISOMY The low birth weight of the puny, malformed infant with trisomy 18 needs no extensive documentation. 31 Weeks prior to the baby's delivery, the obstetrician and the mother may have had suspicions about the baby's being small because of the mother's small gestational weight gain and the observed feeble fetal movements. One series of 90 infants with 18 trisomy reported by Warkany had an average birth weight of 2183 gm. (4 pounds, 13 ounces).33 Half of the gestational periods that were reported were over 40 weeks, the other half being 38 to 40 weeks. Polani reported a mean weight for these infants of 2333 gm. at birth, with an average gestational period of 40.4 weeks. 22 Considering these reports, one finds both prematurity and postmaturity in terms of the length of the gestational period, but, conversely, consistent growth retardation in utero. Utilizing a weight/gestational age analysis, the majority of birth weights in 18 trisomy fall below the tenth percentile for a given gestational age. 25 The placenta in 18 trisomy has been noted to be "small" by some observers,27 but the data remain too scanty to draw any conclusions about the relationship between placental size and intrauterine growth retardation. In addition to the diminution in size, there have been several reports of pathologic changes, such as areas of patchy fibrosis and focal placental infarctions. 14 The presence of only one umbilical artery is also frequently noted. However, relatively little is known yet concerning the anatomy, let alone the function, of human placentas with any of the chromosome abnormalities. No consistent anatomic malformations or malfunctions of such placentas have been described. Certainly, there might be more subtle biochemical or physiological phenomena which do cause degrees of placental insufficiency.
D} TRISOMY The prenatal growth in DI trisomy is less altered than in 18 trisomy, but a majority of newborns with DI trisomy do have smaller than expected birth weights. Thirty cases analyzed by Warkany according to birth weight/gestation time had an average birth weight of 2480 gm.
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(5 pounds, 7112 ounces).33 Most of the infants were born at 38 to 4.0 weeks of gestation. Polani's review showed a mean fetal weight in the Dl trisomy syndrome of 2485 gm., with an average gestation of 38.4 weeks. 22 As is found among children with Down's syndrome, there is no association between intrauterine growth retardation and congenital malformations. The birth defects related to this syndrome are distributed throughout the entire weight range. The unreliability inherent in predicting phenotypic expression of chromosomal mosaicism is true of intrauterine growth as well as of other traits. One would expect a modifying effect on the various somatic defects in individuals with a mosaic complement. Pfeiffer did find a small group of infants with normal-D1 trisomy mosaicism to have a significantly higher mean birth weight than another group of full-term infants with "regular" Dl trisomy.23 Yet there is no consistent relationship between birth weight and "dosage" of cytogenetic abnormality. In Down's syndrome, there generally has been no significant difference found between the birth weights of trisomy 21 infants and trisomy 21-normal mosaics.
THE AUTOSOMAL DELETION SYNDROMES Among newborns with chromosomal deletion syndromes, intrauterine growth is impaired generally, although there is great variability. As mentioned before, the impaired fetal growth in the individual with a loss of genetic material is most likely an intrinsic defect of the developing embryo. Evidence for an abnormal placenta or a nutritional problem is lacking, as pointed out for the autosomal trisomy syndromes.
Figure 2. An example of the low birth weight for term baby is this infant with "antimongolism," partial monosomy of a G group chromosome. Birth weight at term was 4 pounds, 7 ounces. The flexed extremities held off the mattress and the well-equipped chest are consistent with a term baby, rather than a premature infant. (From Reisman, L. E., et al.: Antimongolism. Studies in an infant with a partial monosomy of the 21 chromosome. Lancet, 1 :394, 1966.)
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Seventy per cent of infants with the cri du chat (crying cat) syndrome - for which there is a deletion of part of the short arms of chromosome 5-have birth weights below the tenth percentile. Gestational periods, on the other hand, most often are within the normal range. Many case reports do not discuss birth weight, let alone give an estimate of gestational age, of newborns with the various chromosomal abnormalities. The pattern of low birth weight, accompanied by postnatal growth retardation, however, is highlighted in the recognized syndromes as well as in the more exotic structural chromosome aberrations. Thus, in "antimongolism," in other partial or total deletions of a G group chromosome, in the short-arm 18 deletion syndrome, and in the "ring chromosome" anomalies, intrauterine growth retardation is a common, if not always constant, finding (Fig. 2). Migeon was reminded of the "minute" deletions in Drosophila which, although present on the various autosomes and the X chromosome, cause phenotypically similar aberrations in the affected flies. 16 Decreased body size and developmental retardation are among the anomalies. In man, gene loci requisite for protein synthesis may be scattered on different chromosomal deletions and lead to common phenotypic aberrations. THE SEX CHROMOSOME ABNORMALITIES The baby with the Turner (45/XO) syndrome often is very small for gestational age. One third of these newborns are under 2500 gm. at birth. Short stature almost invariably is present in the child and adult with this abnormality.lo. 31 The 45/XO female generally is below the third percentile in height and only in exceptional cases will achieve a height of 5 feet. (Prenatal and postnatal growth retardation are associated also with the "male Turner's syndrome" or Noonan's syndrome, which probably represents a genetic disorder rather than a gross chromosomal error.) The deficiency of the X chromosome in Turner's syndrome results in the faulty gonadal anlage and the somatic findings which include dwarfism. As shown for the autosomal chromosome abnormalities, prenatal growth retardation and other malformations found in Turner's syndrome have been attributed to the chromosome imbalance. Certainly, the presence of nonspecific congenital heart disease, and short stature, would support this view. The evidence suggests, however, that, although the long arm of the X chromosome is necessary for normal ovarian development, it is less crucial for normal stature and prevention of the other somatic malformations.2.17.18 The few patients with the short arm of the X chromosome intact, such as those with a short arm X isochromosome, have been reported to have normal heights and few somatic anomalies. They still have defective ovaries. On the other hand, the more common isochromosome abnormality with retention of both long arms of the X - and loss of the short arms -leads to the dwarfism and the other typical stigmata of Turner's syndrome. 24
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Thus, loss of the short arm of the X appears related directly to the intrauterine and postnatal stunting. Information involving linear growth (as well as to the Xga blood group and color vision factors, for example) probably resides on the short arm of the X chromosome. Comparable genetic information must be at homologous loci on the Y chromosome, since it seems that double doses of these genes are needed for normal prenatal and postpartum development. One or, as is more likely, more genes on the X and Y chromosomes probably deal specifically with growth. The 47/XYY and 48/XXYY males would have three and four doses respectively of the homologous genetic factors, at least at an early stage of embryonic development. This might explain the excessive height of these individuals. A quantitative relationship of normal X chromosome to somatic anomalies is indicated also by the finding that many XO/XX and XO/XX/ xxx mosaic individuals have normal growth and relatively few defects, but retain the "streak" ovaries of Turner's syndrome. IS The modifying effect of chromosomal mosaicism on intrauterine growth and the various congenital anomalies that were suggested previously in the autosomal trisomy syndromes are more obvious in the Turner abnormality.
THE POLY-X SYNDROMES Unlike her Drosophila melanogaster counterpart, the human triple-X female generally does not have imy growth retardation or other clinically recognizable somatic abnormalities. The same is true of the few XXXX and XXXXX females who have been reported. It should be pointed out, however, that profound mental retardation may be present. The Lyon hypothesis might explain the relatively minor effects of the extra X chromosomes. The genetic inactivation associated with heterochromatinization of the X chromosome may render these abnormalities less deleterious to the developing embryo than those errors involving autosomes. Individuals with Klinefelter's syndrome (47/XXY) reveal no physical stigmata at birth or prenatally. The XXXXY males often do have a severe degree of growth retardation, but intrauterine growth failure and, consequently, short stature are not consistent findings among persons with this abnormality.
DISORDERS WITH CHROMOSOME BREAKAGE Patients with Fanconi's anemia and those with Bloom's syndrome (an unusual dermatologic disorder) have several findings in common. They have low birth weights for their gestational ages, stunting of growth, varied congenital anomalies (more marked in the Fanconi anomaly), and a striking susceptibility to leukemia. Cytogenetic studies of lymphocytes, bone marrow cells, and fibroblasts derived from the skin of affected persons with both diseases are similar. There is no abnormality of chromosome number, but instead there are chromosome breaks and structural rearrangements. These structural anomalies,
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although not specific to these disorders, have become pathognomonic findings in both Bloom's syndrome and Fanconi's anemia. It is possible that the intrauterine growth retardation and dwarfing, along with the other birth defects, and the susceptibility to both chromosome breakage and leukemia, are some of the effects of the mutant pleiotropic genes. It seems more exciting to speculate that the developmental errors in the fetuses with the Fanconi and Bloom syndromes are due to the lethal effect of the damaged chromosomes on the cells of the early embryos.15 The generalized cellular dysplasia might lead on the one hand to defects in cell and tissue growth and metabolism, and on the other hand to malignant transformation.
GENERAL COMMENTS It is clear that intrauterine growth retardation, as well as postnatal stunting, are prominent features among almost all of the syndromes involving autosomal chromosome aberrations and among the XO and XXXXY sex chromosome disorders. Although it is possibly more severe in the 18 and DI trisomy syndromes, fetal growth arrest is consistently associated with all of the commonly recognized chromosomal syndromes and with the more unique structural abnormalities. But, although one has a little more insight into the background of some infants with low :1irth weight for gestational age, the explanations for the growth failure remain conjectural. Since growth after birth is subject to a host of interacting factors, it is not unreasonable to suggest that the prenatal growth of infants (both normal and with chromosomal abnormalities) is also dependent upon various factors. The significance of genetic factors in intrauterine growth, including the individual's own background, has not been discussed. Mentally retarded children without chromosome abnormalities have a significant, if not as marked, degree of growth retardation. 19 Such determinants are important factors, even in those fetuses with chromosomal aberrations. The final height of an individual with Down's syndrome, while markedly deficient, does show a relationship with parental heights, a demonstration that these genetic factors remain operative. It is obvious also that the prenatal growth retardation associated with chromosomal abnormalities is part of a continuum of events affecting the fetus. The failure of orderly mechanisms of cellular division leads to a failure of orderly development of the embryo. The deletion or inactivation of gene loci generally involving protein synthesis, or of specific genes relating to stature, or a nonspecific imbalance due to superfluous or deficient amounts of genetic material, may lead to the abnormal embryologic phenomena. The continuum of growth failure in the abnormal fetus is characterized initially by early embryonic wastage. Evidence for the lethality of the chromosomal genetic imbalance is the finding in spontaneous abortions, which have 20 per cent abnormal karyotypes. In one of Carr's early studies, he reported that chromosome abnormalities were found in early specimens of aborted offspring. 7 In all cases, the embryo (if
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recognizable) lagged in development behind that expected from the estimated gestational period. An asynchromy in development of limb buds and other organs was noted also. The incidence of such anomalies is roughly 1 :250 at birth. It is estimated that 90 per cent of abnormal conceptuses are eliminated as abortuses; the remainder survive as abnormal infants. The impaired viability and development of the abnormal fetuses after birth are related to the early deaths in the perinatal period and to the shortened survival periods almost universally found. There is also an increased incidence of stillbirths and neonatal deaths associated with intrauterine growth retardation which is recognizable but shows no chromosome alteration. 5 ,32 The growth potential of surviving individuals is also affected by hereditary intrauterine growth retardation. The chance of survival in 18 trisomy is 70 per cent to 1 month, 10 per cent to 1 year, and 1 per cent to 10 years. 34 Thus, the surviving individuals with intrauterine growth retardation only represent a small proportion of the original abnormal zygotes.
SUMMARY Intrauterine growth retardation is almost a sine qua non of the recognized chromosome abnormalities, with the exception of the poly-X and Klinefelter's syndromes. Growth arrest is most accentuated in the 18 and Dl trisomy syndromes, but it is still a significant finding in most of the other aberrations, including Down's syndrome and Turner's syndrome. The mechanisms for growth arrest in the chromosomal anomalies remain speculative, but it is clear that growth retardation in utero is a continuum of the intrinsic fetal failure of development which leads to abortions, stillbirths, early neonatal and perinatal death, and, for the survivors, a failure to thrive, markedly diminished lifespans, and, during life, inability to live normally.
REFERENCES 1. Avery, A., Satina, S., and Rietsema, J.: Blakeslee: The Genus Datura. New York, The Ronald Press, 1959. 2. Barr, M. L.: The sex chromosomes in evolution and in medicine. Canad. Med. Assoc. J., 95:1137,1966. 3. Benda, C. E.: The Child with Mongolism. New York, Grune & Stratton, 1960. 4. Bloom, G. E., Warner, S., Gerald, P. S., and Diamond, L. K.: Chromosome abnormalities in constitutional aplastic anemia. New Eng. J. Med., 276:8, 1966. 5. Brent, R L., and Jensh, R P.: Intra·uterine growth retardation. In Woollam, D. H. M., ed.: Advances in Teratology. London, Logos Press, 1967. 6. Bridges, C.: Nondisjunction as proof of the chromosome theory of heredity. Genetics, 1: I, 1916. 7. Carr, D. H.: Chromosome studies in abortuses and stillborn infants. Lancet, 2:603,1963. 8. Falkner, F.: General considerations in human development. In Falkner, F., ed.: Human Development. Philadelphia, W. B. Saunders Co., 1966. 9. Fankhauser, G., and Humphrey, R R: The origin of spontaneous heteroploids in the progeny of diploid, triploid, and tetraploid axolotl females. J. Exp. Zool., 142:379,1959. 10. Federman, D. J.: Abnormal Sexual Development. Philadelphia, W. B. Saunders Co., 1967. 11. Ford, C. E.: Chromosomal abnormality and congenital malformation. In Ciba Foundation Symposium on Congenital Malformations. London, J & A. Churchill, 1960. 12. Gustavson, K. H.: Down's Syndrome: A Clinical and Cytogenetical Investigation. Uppsala, Almquist & Wiksell, 1964.
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13. Hall, B.: Mongolism in newborns. Acta. Paed., suppL 1, 1964, p. 154. 14. Hecht, F.: The placenta in trisomy 18 syndrome. Obstet. Gynec., 22:147,1963. 15. Hirschhorn, K.: Cytogenetic alterations in leukemia. In Perspectives in Leukemia. New York, Grune & Stratton, 1968. 16. Migeon, B. R.: Short arm deletions in group E and chromosomal "deletion" syndromes. J. Pediat., 69:432, 1966. 17. Moore, K. L.: Sex chromatin and gonadal dysgenesis. In Moore, K. L., ed.: The Sex Chromatin. Philadelphia, W. B. Saunders Co., 1966. 18. Morishima, A., and Grumbach, M. M.: The interrelationship of sex chromosome constitution and phenotype in the syndrome of gonadal dysgenesis and its variants. Ann. N.Y. Acad. Sci., 155:695,1968. 19. Mosier, H. D., Jr., Grossman, H. J., and Dingman, H. F.: Physical growth in mental defectives. A study in an institutionalized population. Pediatrics (SuppL), 36:465, 1965. 20. Oster, J.: Mongolism: A clinic genealogical investigation comprising 526 mongols living on Seeland and neighboring islands in Denmark. Copenhagen, Danish Science Press, 1953. 21. Penrose, L. S., and Smith, G. F.: Down's Anomaly. London, J. & A. Churchill, 1966. 22. Polani, P. E.: Chromosome anomalies. Ann. Rev. Med., 15:93, 1964. 23. Pfeiffer, R. A.: Inborn autosomal disorders: The phenotype of autosomal aberrations. In Proceedings of the Third International Congress of Human Genetics. Baltimore, Johns Hopkins Press, 1967. 24. Reisman, L. E., and Matheny, A. P., Jr.: Genetics and Counseling in Medical Practice. St. Louis, C. V. Mosby, 1969. 25. Schutt, W.: Foetal factors in intrauterine growth retardation. In MacGregor, W. G., ed.: Gestational Age, Size and Maturity. London, National Spastics SOCiety and Heinemann Medical Books, 1966. 26. Smith, A., and McKeown, T.: Prenatal growth of mongoloid defectives. Arch. Dis. Child., 30:257, 1955. 27. Smith, D. W., Patau, K., Therman, E., and Inharn, S. L.: The no. 18 trisomy syndrome. J. Pediat., 60:513, 1962. 28. Smithells, R. W.: Chromosomes and the clinician. In Hamerton, J. L., ed.: Chromosomes in Medicine. London, National Spastics Society and Heinemann Medical Books, 1962. 29. Southwick, W. E.: Time and stage in development at which factors operate to produce mongolism. Amer. J. Dis. Child., 57:68, 1939. 30. Usher, R., and McLean, F.: Intrauterine growth oflive-born caucasian infants at sea level: Standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J. Pediat., 74:901, 1969. 31. Valentine, G. H.: The Chromosome Disorders. An Introduction for Clinicians. London, Heinemann Medical Books, 1966. 32. Warkany, J., Monroe, B. B., and Sutherland, B. S.: Intrauterine growth retardation. Amer. J. Dis. Child., 102:249, 1961. 33. Warkany, J., Passarge, E., and Smith, L. B.: Congenital malformations in autosomal trisomy syndromes. Amer. J. Dis. Child., 112:502, 1966. 34. Weber, W. W., Manunes, P., Day, R., and Miller, P.: Trisomy 17-18 (E): Studies on longterm survival with report of two autopsied cases. Pediatrics, 34:533, 1964. Jefferson Medical College Philadelphia, Pennsylvania 19107