One concept of a birth defect in humans is a phenotypic alteration(s) that results in handicapping conditions and significant medical problems.
A genetic basis has been listed for about 1,800 distinguishable phenotypic alterations in humans.1 Many of these conditions are clinically recognizable; others require the use of cytogenetic or biochemical techniques. With the advent of prenatal diagnosis, comprehensive genetic counseling, and various forms of therapy, it is imperative that affected individuals be accurately diagnosed.
The exact diagnosis of any disease or aberration i s essential before genetic counseling can be undertaken. It is not simply a matter of academic interest to characterize a syndrome or exactly diagnose a cytogenetic aberration nor is it only a tool for prognosticating the future course of a patient's condition. Once an exact diagnosis has been established, recurrence risks can be predicted and the family can be given a clear picture of what to expect in future pregnancies.
It is not uncommon for a family with several normal children, in which the parents are in relatively advanced childbearing years (35+), to react to the birth of an abnormal child with no desire for genetic investigation and subsequent genetic counseling. Their immediate and often impulsive response is that they are not planning on having more children anyway and that the birth of this abnormal child has solidified that position. However, once it is made clear to the family that a diagnostic and genetic investigation may establish whether or not their unaffected children and other family members have an increased risk of having abnormal offspring, they usually become anxious to establish the nature of the abnormality. Many families have expressed gratitude for receiving a written report, which can be kept for future use when their children become older and marry, especially when this report indicates that the children have no increased risk of having affected offspring.
The range and diversity of the genetic causes of birth defects are extremely broad, as indicated by the general outline of Table I. The physician who deals with a child with a birth defect must often use his or her clinical expertise, the service and evaluation of consultants, and specialized laboratory procedures. Detailed family histories and pedigrees, in conjunction with a complete physical examination, aid in the elucidation of a genetic basis.
With the elaboration of differential chromosomal staining techniques, it is now possible to more exactly identify each chromosome by its specific banding pattern. Moreover, many structural chromosomal abnormalities that result in phenotypic abnormalities and that might not have been detected with the usual staining methods can now be seen with banding techniques.
Although the finding of a chromosome aberration is usually of great importance, the failure to detect an abnormality does not exclude a genetic basis for the birth defect in question. Even under the most ideal conditions and with the use of the differential staining techniques, the methods may still be too crude to detect submicroscopic structural changes in chromosomes.
Moreover, single gene disorders which are transmitted along Mendelian lines of inheritance are not associated with specific chromosomal aberrations and require other parameters for diagnosis. A detailed discussion of the laboratory diagnosis of genetic disorders is not within the scope of this paper, but two recent articles deal comprehensively with the subject.2'3
For birth defects with a recessive mode of inheritance, the ability to detect the carrier state has great significance. For example, in Tay-Sachs disease (GM2 gangliosidosis, type 1), the homozygote has a total absence of hexosaminidase whereas the heterozygous carrier of the gene has a reduced enzyme level (although clinically unaffected), which is detectable by hexoaminidase assay of the white blood cells.4 If both parents are hétérozygotes, there is a one in four (25 per cent) risk of any pregnancy resulting in an affected child.
When the carriers can be specifically detected, these risks can be made clear prior to the birth of an affected child. In a disease such as cystic fibrosis, for which carrier detection is not yet possible, only the birth of an affected child indicates that the parents are hétérozygotes and have a 25 per cent risk of recurrence.
Polygenic inheritance is difficult to prove because it is mainly the result of slight variations at multiple gene loci, no one of which can completely account for the phenotypic abnormality. Polygenic inheritance is responsible for several localized anomalies (Table 2) that represent about 47 per cent of obvious malformations in early infancy.3 The risk of recurrence for the same type of polygenic defect in offspring from unaffected parents ranges from two to five per cent.5·"'7
There are some birth defects which are so severe that habilitation is precluded despite the most modern of therapeutic modalities. These defects represent more than just a "risk" to the involved families. They are a significant burden, measured in terms of tragedy, emotional upheaval, and financial cost to the family and society. For these untreatable and hopeless disorders, prevention by means of prenatal diagnosis may be the only means by which a family can eliminate the severe burdens represented by them, provided that this does not pose moral and ethical issues which they cannot resolve.
Prenatal diagnosis should be reserved for families who express a willingness to terminate a pregnancy by therapeutic abortion should an abnormal fetus be detected (Table 3). There is no reason to undertake prenatal diagnosis if the birth defect is not going to be prevented. Living for six months with the knowledge that the fetus is severely abnormal is counterproductive, and preparations and adjustments for having an abnormal child are neither helpful nor necessary.
Amniocentesis should not be refused to a couple if they are uncertain about terminating the pregnancy, and no one should be obligated or contract in advance to have a therapeutic abortion in the event an abnormal fetus is detected. Those families who have had direct experience with a devastating birth defect and who seek prenatal diagnosis have usually clearly decided to terminate the pregnancy should recurrence of the abnormality be detected.
Exfoliated fetal cells obtained from the amniotic fluid can be used for cytogenetic studies or biochemical and enzymatic studies. The number of metabolic diseases that can be prenatally diagnosed is rapidly growing/·9' 10>11 and it is impractical to routinely test for any metabolic disease other than the one for which there is a risk. However, since chromosome aberrations occur in one in 150 live births/2·13 it is reasonable and practical to do a chromosome analysis at the time of testing for a specific metabolic disease with a known risk.
GENETIC CAUSES OF BIRTH DEFECTS
CONDITIONS WITH POLYGENIC INHERITANCE
INDICATIONS FOR PRENATAL DIAGNOSIS
Prenatal diagnosis can reduce nearly to zero a known risk of 25 per cent for an autosomal recessive disease, a 50 per cent risk for an X-linked disease (if the fetus is a male), or a high chromosome risk. It is important to emphasize to the families at risk that reducing their known risk to zero1 does not guarantee or assure them that the fetus will be entirely normal. Many couples feel that if the amniotic fluid culture yields normal results, their baby will be normal. It must be made clear that once their specific risk is reduced to zero, they have the same risk as the population at large with regard to all other problems. In addition, an informed consent which spells out potential problems and pitfalls with regard to prenatal diagnosis is now being used by many laboratories.
For conditions which result in abnormal morphogenesis but which have no specific chromosomal or biochemical/enzymatic abnormalities, direct visualization of the fetus, using an instrument such as an amnioscope for amniotic endoscopy, holds promise. Since most structural defects of this type are polygenic in nature with a two to five per cent recurrence risk, the safety of amnioscopy must be fully established before widespread use is possible.
Prenatal diagnosis and subsequent prevention of birth defects has stimulated great interest and is sure to be refined and more widely used in the future. The moral, ethical, and religious problems generated by this technique must be dealt with on an individual basis since there are no clear and easy solutions.
Since the basic processes of morphogenesis are genetically controlled, it is not surprising that genetic aberrations are a major cause of birth defects. This article has been intended to provide a general clinical approach to and an appreciation of the complexity and diversity of the genetics of birth defects. Q
1. McKusick. V. MendeHan inheritance in Man, Third Edition. Baltimore: Johns Hopkins Press. 1971.
2. Shapiro, L. R- The cytogenelics laboratory in pediatrics. Pediat. Clin. N. Amer. 18 (1971), 209.
3. Thomas, G. H. and Scott, C. I., Jr. Laboratory diagnosis of genetic disorders. Pediat. Clin. N. Amer. 20 (1973), 105.
4. Okada, S., Veath, M. D.. Leroy, J., and O'Brien, J. S. Ganglioside GM2 storage diseases. Hexosaminidase deficiencies in cultured fibroblasts. Amer. J. Hum. Genet. 23 (1971), 55.
5. Smith, D. W. Recognizable Patterns of Human Maltormation. Philadelphia: W. B. SaundersCo.. 1970,316.
6. Carter, C. O. The inheritance of common congenital malformations. Prog. Med. Genet. 4 (1965), 59.
7. Smith, D. W. and Aase, J. M. Inheritance of common malformations. J. Pediat. 76 (1970), 653.
8. Milunsky, A., et al. Prenatal genetic diagnosis. New Eng. J. Med. 283 (1970), Part 1, 1370-1381; Part 2, 1441-1447; Part 3, 1498-1504.
9. Milunsky, A. and Littlefield. J. W. Prenatal diagnosis of inborn errors of metabolism. Ann. Rev. Med. 23 (1972). 57.
10. Nadler, H. L. Antenatal detection of hereditary disorders. Pediatrics 42 (1968), 912.
11. Howell, R. R. Prenatal diagnosis. Pediat. Clin. N. Amer. 20 (1973), 141.
12. Ratcliffe, S., Stewart, ?., Melville, M., Jacobs, P., and Keay, A. J. Chromosome studies on 3.500 newborn male infants. Lancet 1 (1970), 121.
13. Sergovish, F., Valentine. M. B., Chen. A. T. L.. Kinch, R. A. H.. and Smout. M. S. Chromosome aberrations in 2,1 59 consecutive newborn babies. New Eng. J. Med. 280 (1969), 851.
GENETIC CAUSES OF BIRTH DEFECTS
CONDITIONS WITH POLYGENIC INHERITANCE
INDICATIONS FOR PRENATAL DIAGNOSIS