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Historical Review and Recent Advances
in Neonatal and Perinatal Medicine

Edited by George F. Smith, MD and Dharmapuri Vidyasagar, MD
Published by Mead Johnson Nutritional Division, 1980
Not Copyrighted By Publisher

Chapter 20

Congenital Abnormalities and Genetic Concepts in Neonatology

George F. Smith, M. D.


Congential abnormalities, both physical and mental, in infants, have been the concern of physicians and society for many centuries. Hippocrates (C. 460-375 B.C.) described anencephaly and other types of cranial deformities in infants. There have been considerable differences in how defective infants have been cared for in different societies. For example, in Sparta, under the laws of Lycurgas, infants with defects shared the same fate as weakly infants-who were allowed to perish from exposure or were thrown into the Eurotas River. Some primitive societies, even up until modern times, exercised the same type of practice on deformed or handicapped infants. In Ancient Rome, the law provided for the killing of malformed or weakly infants, though mentally defective infants and children were tolerated, if they had value for amusement of diversion.

A variation of these ancient practices occurred under the Nazi regime during World War II and can be found in primitive societies even in modern times. During the medieval period, superstitions and witchcraft often dictated a harsh fate for the defective infant. It was during the middle ages that attitudes changed and usually these changes developed from religious beliefs. We then began to see salvation for the defective infant. Still, not all the fruits of religious beliefs were protective of these infants since, on occasion, deformed infants or children were viewed as products of the devil, or as an indication of God's wrath which then justified the destruction of the infants. An example of these unusual religious attitudes is found in the first congenital abnormality recorded in the United States which occurred October 17, 1637 in the Massachusetts Bay Colony.[1] Mary Doyer (D. 1660) gave birth to an anencephalic stillborn infant. Anne Hutchinson (C. 1591-1643), a midwife and religious individual, was present at the delivery but did not attend the mother. Both women were rebuked by civil and religious authorities which viewed the "monstrous" infant as a sign of God's condemnation of Anne Hutchinson's religious views. In the beginning, a protective attitude was more characteristic of Eastern than of Western religions. Confucius and Zoroaster instructed their followers to care for the weak-minded and to treat them kindly.

With the development of Christianity in Europe, the status of the handicapped infant and child began to improve and, on occasion, they were given homes in the monasteries. Real progress was made during the reigns of Edward I (C. 1272-1307) and Edward II, (C. 1307-1327) when laws were enacted protecting the estates of retarded and handicapped individuals.[2]

From the sixteenth century through modern times, severe congenital abnormalities were of major interest to, at first, the anatomists and, later, the pathologists. Elaborate drawings can be found in sixteenth and seventeenth century pathological anatomy text books. While many of the drawings are aesthetically pleasing, they did nothing to increase the knowledge about the causation of the defects nor did they offer any suggestions on how the conditions could be prevented.

By the mid-nineteenth century, anatomical descriptions began to be replaced by speculations on the causes of congenital abnormalities in infants and children; however, most of these speculations were not accompanied by any solid scientific data. Interest in human birth defects was also stimulated by observations of congenital defects in animals and empirical breeding practices that were being performed on domestic animals. John Hunter (C. 1728-1793), the English surgeon, initiated the work with animals which would later be called comparative anatomy. From these studies developed the work that led to a comparison of congenital abnormalities between animals and man. It was during this period that the placental circulation was first described and the argument still exists, which of the brothers -- John Hunter or his brother, the obstetrician, William Hunter (C. 1718-1783) -- first described the placental circulation.

While the new concepts of evolution and natural selection in 1859 by Charles Darwin (C. 1809-1882) and Wallace (C. 1823-1913) were not directly related to congenital abnormalities, a new era of biological thinking did begin which permitted a much more scientific approach to the problem. It was during the latter part of the nineteenth century that Galton (C. 1822-1911), Darwin's cousin, established the mathematical and statistical principles through which normal variations in man could be scientifically evaluated.

In 1866 Gregory Mendel's (C. 1822-1884) paper on the principles of genetic transmission of inherited characters was published. Mendel's laws of segregation, which would have established the cause of certain types of congenital abnormalities, were unknown to the general scientific community until they were rediscovered 34 years later, in 1900. Had the genetic principles enumerated by Mendel been known at the time, the science of congenital abnormalities would have shown real progress during the second half of the nineteenth century. As it turned out, it was not until 1902 that the pediatrician, Archibald Garrod (C. 1858-1936), first applied the recessive genetic principles of Mendel to the human disease, alcaptonuria.[3] It was actually William Bates (C. 1861-1926), the English biologist, who was one of the few individuals at that time who saw the relationship of Mendel's principles to human disease and directed Garrod in the correct interpretation of his clinical data in humans. Without the genetic principles established by Mendel there could be no scientific understanding of the genetic causes of congenital abnormalities.

During the early part of this century, surgical techniques were developed for the treatment and, in some instances, correction of a small number of congenital abnormalities. At the same time, increased efforts were being made to aid the survival of these infants during the neonatal period. However, any attempt at an understanding of the causes or any application of preventive measures in general was viewed as being beyond the scope of medical knowledge at the time.

During the first quarter of the twentieth century there was speculation on environmental factors, particularly infectious diseases, as the cause of some congenital abnormalities, but there was a dearth of good ideas and scientific data. It was not until Gregg (C. 1892-1966) in 1941 published his paper on the teratogenic effects of the rubella virus on the newborn[4] did there occur an awakening to the adverse effect of environmental factors on the developing fetus. Later Lenz, in 1962, in Germany,[5] and McBride, in 1961, in England,[6] alerted the world to the teratogenic effects of the drug thalidomide.

Lejeune, in 1959,[7] demonstrated the first association of the physical and mental abnormalities in Down syndrome with an autosomal chromosomal abnormality. This was followed by an avalanche of descriptions of syndromes associated with chromosomal abnormalities. Geneticists in the 1920's and 30's did not consider the chromosome to be a major source of congenital abnormalities, since they did not think that human chromosomes could be mutated at a high enough rate to be a contributing factor. It was in 1965 that Carr[8] gave us some idea of the amount of fetal damage that was caused by chromosomal changes in spontaneously aborted fetuses. He showed that in 40-50% of all spontaneous abortions there was a major chromosomal abnormality occurring in the fetus.

The demonstrations by Steele and Breg (1966)[9] and Jacobson and Barter (1967)[10] that chromosomal abnormalities could be detected in the fetus without harm to the pregnancy initiated the concept of cytological prenatal diagnosis which may eventually lead us to prenatal treatment.

An estimate of the causes of birth defects was reported by Wilson in 1977.[11] Wilson demonstrated that in only one-third of all the congenital abnormalities is it possible to make an etiological diagnosis; and in 65-70% of the cases an etiological cause goes undetected. It is of significance that when etiological diagnosis is made, diseases caused by a genetic factor account for 20% of the cases.

The never ending search for the cause of birth defects is predicated on the fact that an identification of a curse has implicit in it that a cure will follow. Ira many cases of birth defects the `causes and cures' concept has not applied.[12] While the "causes and cures" thinking has been fruitful when dealing with infectious diseases, with birth defects the solutions seem to be much more complicated. For example, the discovery of the extra chromosome in Down syndrome twenty-two years ago has failed to produce a cure or lead to a program of prevention -- the exception, of course, being amniocentesis.

One way we can get some insight into the proportion of causes of congenital abnormalities in the newborn is from the data on the causes of severe mental deficiency (SMD) in infants and children.

In severe mental deficiency, the I.Q. is 50 or below. The mean prevalence rate is 4 per 1,000 children (range 2.8 to 5.4 per 1,000). It has been estimated that between 1-2% of all newborn infants are potentially retarded. Affected newborns with an I. Q. of less than 25 will have a 90% mortality rate: within the first 5 years of life. Survival figures for this group of infants will vary greatly depending on the type of medical services that are available at the time of birth and during infancy and early childhood. For the I.Q. range of 25-30, the mortality rate is less, approximately 50% during the first 5 years of life. In adults age 20 years and older, severe mental deficiency occurs much less frequently than in childhood, at approximately .04 per 1,000 adults. This marked reduction in prevalence of' severe mental deficiency in adults is a reflection of the high death rate that occurs in this population starting in early infancy and childhood.

Severe mental deficiency can be divided generally into the following etiological groups:[13] Those produced by Mendelian genetic factors represent tire largest group and account for 21.5-35% of all the cases; chromosomal abnormalities 20%; exogenous factors 30%; and unknown causes 10-15% (see Table 1).



Table 1

Causes of Severe Mental Deficiency











*Figures do not add up to100 per cent, since they represent a summation of various studies.



Genetic Mendelian traits which account for 21.5-35% of all the individuals with severe mental deficiency are represented in the following proportions, namely, dominant traits account for 21%, recessive traits, which are exactly double the dominant traits, account for 42% and X-linked traits, 37%. In terms of the total numbers of severely mentally deficient children, dominant traits account for 4.5% of the individuals, recessive traits 9% and X-linked 8% (see Table 2).



Table 2

Mendelian Causes of Severe Mental Deficiency (SMD)


Percentage of Genetic Causes

Percentage of All Causes of SMD















Chromosome abnormalities account for approximately 20% of the severely mentally deficient population. The congenital abnormalities that are produced are due to quantitative imbalances in gene dosage effect, rather than being the result of an abnormal gene. Abnormalities of the chromosomes are due to numerical or structural imbalances of the autosome or sex chromosomes. For example, in Down syndrome, there is an extra number 21 chromosome and in the Cri du Chat syndrome a piece of the upper segment of the number 5 chromosome is missing. In general, absent genetic material tends to be more damaging than extra genetic material.

The damaging effects of chromosomal imbalance are best demonstrated when the chromosomes of spontaneously aborted fetuses are examined.

Approximately 40% of aborted fetuses have a chromosomal abnormality which is lethal during the early months of gestation. In Down syndrome, for every infant born alive, two Down syndrome fetuses are spontaneously aborted.[14] Chromosomal abnormalities occur in approximately 1 in 200 non-selected births, 2 in 100 full-term births and 2 in 100 full-term infants born with a low birth weight. Approximately 5-6 out of every 100 infants dying in the perinatal period have a chromosomal abnormality.


Early prenatal abnormalities account for approximately 13% of the severely mentally deficient population. It is a poorly defined group and contains such known conditions as neural tube defects, de Lange, Rubinstein-Taybi and the Sturge-Weber syndromes, cerebral gigantism, hypercalcemia, dwarfism and skull abnormalities. Not much is known about the causes of these defects but the causes may include teratogens and detrimental environmental agents, chromosomal deletions or rearrangements, fresh mutations, and polygenic and multifactorial genetic factors. In the future, many individuals in this diagnostic category will be reclassified, as we learn more about the causes of mental deficiency.


Perinatal factors account for approximately 10% of severe mental deficiency. As yet, it is difficult to be certain about the cause and effect relationship of severe mental deficiency and unusual events occurring during the perinatal period. As more is learned about fetal placental development, maternal nutrition, neonatal oxygen, and nutritional and environmental needs of the fetus and neonate, we should have a better understanding about how the fetus or neonate can be damaged during this period of development. Perinatal factors producing severe mental deficiency include prematurity, subdural and central nervous system hemorrhage, hypoglycemia, hydrocephalus, hypothyroidism and many other such diagnoses.


Perinatal and postnatal infections account for approximately 13% of severe mental deficiency. The two conditions are nearly equally divided in frequency with perinatal infections occurring slightly more frequently, by 12%. Included in this group are such conditions as rubella, cytomegalic inclusion disease, meningitis, encephalitis, gastroenteritis and septicemia.


Deprivation and injuries account for approximately 2% of severe mental retardation. Included in this category are such conditions as accidental head injury, poisoning and toxins (alcoholism), battered babies, maternal prenatal trauma, starvation and nutritional deficiency.


This category accounts for approximately 21% of severe mental deficiency. With a better understanding of mental deficiency and its causes, an exact diagnosis could be made and the patients classified under one of the other headings.


Mendelian genetic causes, in general, are a factor in approximately one-third of all the patients with severe mental deficiency (see Tables 1 and 2).


Genetically dominant diseases account for approximately 4.5% of all the patients with severe mental deficiency. This is undoubtedly an underestimation but it is the best approximation presently available. This could be an underestimation by as much as 1-3%. There are still many diseases producing severe mental retardation which are not diagnosed and could be caused by a dominant trait; there are others that exist in the population only by fresh mutations which present difficulty in identification. While many of the dominant conditions in this category are due to fresh mutations, each individual dominant disease has its own mutation rate.

For example, in epiloia, or tuberous sclerosis, the inherited form of the disease accounts for 50% of the patients, while the disease caused by fresh mutations accounts for the additional 50% of the patients. In those dominant diseases where the fertility of the affected individual is low, fresh mutations will account for the majority of new cases. In those dominant diseases where the expressivity of the abnormal gene varies greatly, an increasing number of patients will be accounted for by the inherited form of the abnormal gene.

Each dominant disease has its own ratio of fresh mutations to the inherited form of the disease which has to be taken into consideration when evaluating methods of prevention. Some of the more common dominant diseases in this category are Noonan syndrome, tuberous sclerosis, neurofibromatosis, cleidocranial dysostosis, Crouzon and Apert syndromes.


Recessive diseases account for approximately 9% of severe mental deficiency. This category contains many causes of' severe mental deficiency. The diseases in this group range from individuals with severe physical abnormalities to individuals with major biochemical defects. It is to be expected that the types of' diseases in this category will vary from country to country and among different populations. Within this group of diseases, there would be an increased incidence of incest, consanguinity, first-cousin marriages and population inbreeding. Some of the diseases in this category are cerebral degenerative disorders, phenylketonuria, Smith-Lemni-Opitz syndrome, mucopolysaccharidosis, homocystinuria, hyperglycinemia, familial microcephaly, Sjogren-Larsson syndrome, Seckel dwarfism and familial spastic diplegia.


X-linked conditions account for approximately 8% of' severe mental deficiency. The incidence of X-linked diseases producing mental deficiency in males can vary among populations. For example, in New South Wales, 20% of the moderately retarded males were thought to be affected by an X-linked form of' mental deficiency. It is to be expected that the types of' X-linked mental retardation will vary greatly among populations and the following are but a few examples of X-linked diseases occurring in a particular population: Renpenning, Lesch-Nylran and Borjeson-Forssman-Lehmann syndromes, Duchenne muscular dystrophy and some forms of hydrocephalus.

Using both humans and animals, research studies into how congenital abnormalities are produced are beginning to give us a better understanding about some of these conditions. The mouse has been a particularly useful animal model for studying congenital abnormalities. For example, in the mouse the mutant gene pallid, when homozygous, produces animals that have growth abnormalities and ataxia. The ataxia is caused by a faulty development of the otoliths of the inner ear.[15]

Similar ear abnormalities occur in genetically normal mice born of manganese deficient mothers. On the basis o£ these observations, manganese in high concentrations given to mothers of pallid mice during gestation prevents the inner ear deformity.

It is suspected that in both forms of the inner ear abnormality, the deficiency and the mutation, there is an incorporation defect in the muco-polysaccharide matrix of the otolithic membrane.

With the introduction of chromosomal banding and the localization of specific gene sites on chromosomes (see Fig. 1), major breakthroughs are beginning to occur in the field of congenital abnormalities. For example, in Down syndrome, we now know that only the lower 2/3rds of the number 21 chromosome is needed in triplicate to produce, the syndrome[16] and that, as smaller portions of' that segment are present, the physical and mental disabilities associated with the syndrome become less severe -- tending more towards normality.

Three gene loci have now been identified on the lower arm of the number 21 chromosome. They are the enzyme superoxide dismutase (SOD-1), phosphofructosekinase (PFK) [17] and gene controlling interferon receptors (If. Rec.). What we are attempting to understand is the mechanism by which, in trisomic individuals (Down syndrome), an excess of genetic materials produces physical and mental abnormalities.

In Down syndrome there is a dosage effect of SOD-1 whereby the enzyme is increased by 1/3rd the amount which is present in normal individuals. Associated with the increased amount of SOD-1 there is also an increase in the enzyme glutathionperoxidase (GSHPxase) even though the gene locus for this enzyme is on the number 6 chromosome.[18,19] What appears to be happening is that SOD-1 produces hydrogen peroxide (H202) which is a substrate for GSHPxase and accounts for the elevation of this enzyme in this syndrome. It now appears that there is some relationship between intelligence in Down syndrome and the GSHPxase level. It is postulated that the GSHPxase affects the brain chemistry through a lipoid GSHPxase pathway.

The interferon receptor gene (If. Rec.) offers another possible mechanism of action for producing abnormalities in trisomic state. Interferon, a hormone-like substance, has many functions, one of which prevents macrophage maturation. Macrophage interferon receptor sites are increased by 1/3rd in Down syndrome[20] and it now appears that this enhances the inhibition of macrophage maturation and increases the susceptibility to infection for individuals.

Presently, we are past the descriptive stage of fetal and newborn congenital abnormalities. During the 1980's we will see developed more basic ideas about how congenital abnormalities are produced. Developments in cell membrane transfer, cell membrane receptor sites, recombinant DNA studies, plus many others should, by the year 2000 A.D., greatly increase our knowledge about how some of these congenital abnormalities are produced.


Fig. l. Banded chromosomes; male karyotype.


1. Cone T. E.: History of American Pediatrics. Boston, Little Brown & Co., 1978, p. 19.

2. Penrose L. S.: The Biology of Mental Defect. London: Sidgwick & Jackson Limited, 1963, p. 3.

3a. Garrod A. E.: The incidence of alkaptonuria. A study in chemical individuality. Lancet ii:1616-1620, 1902.

3b. Garrod A. E.: The Croonian lectures on metabolism-inborn errors of metabolism. Lecture 1. Lancet ii:1-7, 1908; Lecture 2, Lancet ii:73-79, 1908.

4. Gregg N. M.: Congenital cataract following German measles in the mother. Tr. Ophthalmol. Soc. Aust. 3:34, 1941.

5. Lenz W.: Thalidomide and congenital abnormalities. Lancet i:45, 1962.

6. McBride W. G.: Thalidomide and congenital abnormalities. Lancet ii:1358, 1961.

7. Lejeune J., Gautier M., Turpin R.: Le chromosomes humains en culture de tissus. C. R. Acad. Sci. (Paris) 248:602, 1959.

8. Carr D. H.: Chromosome studies in spontaneous abortions. Obstet. Gynecol. 26:308, 1965.

9. Steels M. W., Breg W. R. Jr.: Karyotyping of human anmiotic cells. Lancet 1:383, 1966.

10. Jacobson C. B., Barter R. H.: Suggested use of amniocentesis for the diagnosis and management of genetic defects. Am. J. Obstet. Gynecol. 99:796, 1967.

11. Wilson J. G.: Teratogenic effects of environmental chemicals. Fed. Proc. 36:1968, 1977.

12. Childs B.: Priorities for research on birth defects. In Littlefield J. W., DeGrouchy J. (eds.): Birth Defects. Amsterdam: Excerpta Medica, 1978.

13. Stein Z., Susser M.: Epidemiologic and genetic issues in mental retardation. In Morton N. E., Chung C. S. (eds.): Genetic Epidemiology. New York: Academic Press, 1978, p. 415.

14. Smith G. F., Berg, J.: Down's Anomaly. London: Churchill Livingston, 1976. 15. Lyon M. F.: Absence of otoliths in the mouse: an effect of the pallid mutant. J. Genet. 51:638, 1953.

16. Williams J. D., Summit R. L., Martens P. R. et al.: Familial Down syndrome due to t(10;21) translocatiow evidence that the Down phenotype is related to trisomy of a specific segment of chromosome 21. Am. J. Hum. Genet. 27:478, 1975.

17. Shobhana V., Francke U.: Assignment of the human gene for liver type phosphofructokinase isozyme to chromosome 21 using somatic cell hybrids. (Abs.) Pediatr. Res. 15:510, 1981.

18. Sinet P. M., Lejeune J., Jerome H.: Trisomy 21 (Down's syndrome) glutathione peroxidase, hexose monaphosphate shunt and IQ. Life Sciences 24:29, 1979.

19. Frischer H., Chu L. K., Ahmad T. et al.: Superoxide dismutase and glutathion peroxidase abnormalities in erythrocytes and lymphoid cells in Down's syndrome. (In press.)

20. Epstein L. B., Lee S. H. S., Epstein C. J.: Enhanced sensitivity of trisomy 21 monocytes to the maturation-inhibiting effect of interferon. Cellular Immunology 50:191, 1980.

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