Human Birth Defects

Numeric Chromosomal Abnormalities

In the United States, approximately 1 in 120 neonates has a chromosomal abnormality. Numeric aberrations of chromosomes usually result from nondisjunction , an error in cell division in which there is a failure of a chromosomal pair or two chromatids of a chromosome to disjoin during mitosis or meiosis (see Chapter 2 , Figs. 2.2 and 2.3 ). As a result, the chromosomal pair or chromatids pass to one daughter cell, and the other daughter cell receives neither ( Fig. 20.5 ). Nondisjunction may occur during maternal or paternal gametogenesis. The chromosomes in somatic cells are normally paired and called homologous chromosomes (homologs). Normal human females have 22 pairs of autosomes plus two X chromosomes, whereas normal males have 22 pairs of autosomes plus one X and one Y chromosome.

Trisomy of Sex Chromosomes

Trisomy of the sex chromosomes is a common disorder (see Table 20.7 ). However, because there are no characteristic physical findings in infants or children, the disorder is not usually detected until puberty ( Fig. 20.12 ). Sex chromatin studies have detected some types of trisomy because two masses of sex chromatin are found in the nuclei of XXX females (trisomy X), and the nuclei of XXY males (Klinefelter syndrome) contain a mass of sex chromatin ( Table 20.4 , and see Fig. 20.12 ). Diagnosis is best achieved by chromosome analysis or other molecular cytogenetic techniques.

Tetrasomy and Pentasomy

Persons with tetrasomy or pentasomy have cell nuclei with four or five sex chromosomes, respectively. Several chromosome complexes have been reported in females (48,XXXX and 49,XXXXX) and in males (48,XXXY, 48,XXYY, 49,XXXYY, and 49,XXXXY). The extra sex chromosomes do not accentuate sexual characteristics. However, the greater the number of sex chromosomes in males, the greater the severity of cognitive deficiency and physical impairment. The tetrasomy X syndrome (48,XXXX) is associated with serious cognitive deficiency and physical development. The pentasomy X syndrome (49,XXXXX) usually includes severe cognitive deficiency and multiple physical defects.

Mosaicism

A person with at least two cell lines with two or more genotypes is a mosaic . The autosomes or sex chromosomes may be involved. The defects usually are less serious than in persons with monosomy or trisomy. For instance, the features of Turner syndrome are not as evident in 45,X/46,XX mosaic females as in the usual 45,X females. Mosaicism usually results from nondisjunction during early cleavage of the zygote (see Chapter 2 , Fig. 2.16 , and page 33 ). Mosaicism resulting from loss of a chromosome by anaphase lagging also occurs. The chromosomes separate normally, but one of them is delayed in its migration and is eventually lost.

Triploidy

The most common type of polyploidy (cell nucleus containing three or more haploid sets; see Chapter 2 , Fig. 2.1 ) is triploid fetus (69 chromosomes). Triploid fetuses have severe intrauterine growth retardation with head–body disproportion (see Fig. 20.6 ). Although triploid fetuses are born, they do not survive very long.

Triploidy most frequently results from fertilization of an oocyte by two sperms (dispermy) . Failure of one of the meiotic divisions (see Chapter 2 , Fig. 2.1 ), resulting in a diploid oocyte or sperm , may account for some cases. Triploid fetuses account for approximately 20% of chromosomally abnormal spontaneous abortions.

Tetraploidy

Doubling of the diploid chromosome number from 46 to 92 (tetraploidy) probably occurs during the first cleavage division of the zygote (see Chapter 2 , Fig. 2.17 A ). Division of this abnormal zygote subsequently results in an embryo with cells containing 92 chromosomes. Tetraploid embryos abort very early, and often all that is recovered is an empty chorionic sac (blighted embryo) .

Table 20.4

Trisomy of Chromosomes

Chromosome Complement *	Sex	Incidence †	Usual Characteristics
47,XXX	Female	1 in 1000	Normal in appearance; usually fertile; 15% to 25% are mildly mentally deficient
47,XXY	Male	1 in 1000	Klinefelter syndrome: small testes, hyalinization of seminiferous tubules; aspermatogenesis; often tall with disproportionately long lower limbs. Intelligence is less than in normal siblings. Approximately 40% of these males have gynecomastia (see Fig. 20.9 ).
47,XYY	Male	1 in 1000	Normal in appearance and usually tall.

* The numbers designate the total number of chromosomes, including the sex chromosomes shown after the comma.

† Data from Hook EB, Hamerton JL: The frequency of chromosome abnormalities detected in consecutive newborn studies; differences between studies; results by sex and by severity of phenotypic involvement. In Hook EB, Porter IH, editors: Population cytogenetics: studies in humans , New York, 1977, Academic Press. More information is provided by Nussbaum RL, Mclnnes RR, Willard HF: Thompson and Thompson genetics in medicine , ed 8, Philadelphia, 2015, Elsevier.

Structural Chromosomal Abnormalities

Most structural chromosomal abnormalities result from chromosome breakage , followed by reconstitution in an abnormal combination ( Fig. 20.13 ). The breakage may be induced by environmental factors such as ionizing radiation, viral infections, drugs, and chemicals. The type of structural abnormality depends on what happens to the broken chromosome pieces. The only two aberrations of chromosome structure that are likely to be transmitted from a parent to an embryo are structural rearrangements, such as inversion and translocation . Overall, structural abnormalities of chromosomes occur in about 1 in 375 neonates.

Deletion

When a chromosome breaks, part of it may be lost (see Fig. 20.13 B ). A partial terminal deletion from the short arm of chromosome 5 causes cri du chat syndrome ( Fig. 20.14 ). Affected infants have a weak, cat-like cry; microcephaly (small neurocranium); severe cognitive deficiency; and congenital heart disease.

A ring chromosome is a type of deletion chromosome from which both ends have been lost and the broken ends have rejoined to form a ring-shaped chromosome (see Fig. 20.13 C ). Ring chromosomes are rare, but they have been found for all chromosomes. These abnormal chromosomes have been described in persons with 45,X (Turner syndrome), trisomy 18 (Edwards syndrome), and other structural chromosomal abnormalities.

Birth Defects Caused by Mutant Genes

Between 7% and 8% of birth defects are caused by gene defects (see Fig. 20.3 ). A mutation , usually involving a loss or change in the function of a gene, is any permanent, heritable change in the sequence of genomic DNA. Because a random change is unlikely to lead to an improvement in development, most mutations are deleterious, and some are lethal .

The mutation rate can be increased by a number of environmental agents, such as large doses of ionizing radiation. Defects resulting from gene mutations are inherited according to Mendelian laws (laws of inheritance of single-gene traits that form the basis of the science of genetics); consequently, predictions can be made about the probability of their occurrence in the affected person's children and other relatives. An example of an autosomal dominant inherited birth defect is achondroplasia ( Fig. 20.15 ), which results from a G-to-A transition mutation at nucleotide 1138 of the cDNA in the fibroblast growth factor receptor 3 gene on chromosome 4p. Other defects, such as congenital suprarenal hyperplasia (see Fig. 20.16 ) and microcephaly (see Chapter 17 , Fig. 17.36 ), are attributed to autosomal recessive inheritance. Autosomal recessive genes manifest only when homozygous; as a consequence, many carriers of these genes (heterozygotes) remain undetected.

Fragile X syndrome is the most commonly known inherited cause of cognitive development disability ( Fig. 20.17 ). It is one of more than 200 X-linked disorders associated with cognitive impairment. Fragile X syndrome occurs in 1 of 4000 male births. Autism spectrum disorders and attention deficit hyperactivity disorder are prevalent in this condition. Diagnosis of this syndrome can be confirmed by chromosome analysis demonstrating the fragile X chromosome at Xq27.3 or by DNA studies showing an expansion of CGG nucleotides in a specific region of the FMR1 gene. Recently, an associated neurodegenerative disorder has also been described: Fragile X tremor/ataxia syndrome.

Several genetic disorders are caused by expansion of trinucleotides (combination of three adjacent nucleotides) in specific genes. Other examples include myotonic dystrophy, Huntington chorea, spinobulbar atrophy (Kennedy syndrome), and Friedreich ataxia. X-linked recessive genes usually manifest in affected (hemizygous) males and occasionally in carrier (heterozygous) females, as in Fragile X syndrome (see Fig. 20.17 ).

The human genome comprises an estimated 20,000 to 25,000 genes per haploid set or 3 billion base pairs. Because of the Human Genome Project and international research collaboration, many disease- and birth defect–causing mutations in genes have been and will continue to be identified. Most genes will be sequenced, and their specific function determined.

Determining the causes of birth defects requires a better understanding of gene expression during early development. Most genes are expressed in a wide variety of cells and are involved in basic cellular metabolic functions, such as nucleic acid and protein synthesis, cytoskeleton and organelle biogenesis, and nutrient transport and other cellular mechanisms. These genes are referred to as housekeeping genes . The specialty genes are expressed at specific times in specific cells and define the hundreds of cell types that make up the human organism. An essential aspect of developmental biology is regulation of gene expression. Regulation is often achieved by transcription factors that bind to regulatory or promoter elements of specific genes.

Epigenetic regulation refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. The mechanisms of epigenetic change are not entirely clear, but modifying transcriptional factors, DNA methylation, and histone modification may be key in altering developmental events. Several birth defects, including neurodevelopmental problems (e.g., autism spectrum disorder), may be the result of altered gene expression due to environmental chemicals, drugs, and maternal stress or altered nutrition rather than changes in DNA sequences.

Genomic imprinting is an epigenetic process in which the allele inherited from the mother or father is marked by methylation (imprinted), silencing the gene and allowing expression of the nonimprinted gene from the other parent. Only the paternal or maternal allele (any one of a series of two or more different genes) of a gene is active in the offspring. The sex of the transmitting parent therefore influences expression or nonexpression of certain genes (see Table 20.5 ).

In Prader–Willi syndrome (PWS) and Angelman syndrome (AS) , the phenotype is determined by whether the microdeletion is transmitted by the father (PWS) or the mother (AS). In a substantial number of cases of PWS and AS and in several other genetic disorders, the condition arises from a phenomenon referred to as uniparental disomy . In PWS and AS, both copies of chromosome 15 originate from only one parent. PWS occurs when both are derived from the mother, and AS occurs when both are paternally derived. The mechanism is thought to begin with a trisomic conceptus, followed by a loss of the extra chromosome in an early postzygotic cell division. This results in a “rescued” cell in which both chromosomes have been derived from one parent.

Uniparental disomy has involved several other chromosome pairs. Some are associated with adverse clinical outcomes involving chromosome 6 (transient neonatal diabetes mellitus) and 7 (Silver–Russell syndrome), whereas others (chromosomes 1 and 22) are not associated with abnormal phenotypic effects.

Homeobox genes are found in all vertebrates and have highly conserved sequences and order. They are involved in early embryonic development and specify identity and spatial arrangements of body segments. Protein products of these genes bind to DNA and form transcriptional factors that regulate gene expression. Disorders associated with some homeobox gene mutations are described in Table 20.6 .

Developmental Signaling Pathways

Normal embryogenesis is regulated by several complex signaling cascades (see Chapter 21 ). Mutations or alterations in any of these signaling pathways can lead to birth defects. Many pathways are cell autonomous and alter the differentiation of only that particular cell, as seen in proteins produced by HOXA and HOXD gene clusters (in which mutations lead to a variety of limb defects). Other transcriptional factors act by influencing the pattern of gene expression of adjacent cells. These short-range signal controls can act as simple on-off switches (paracrine signals) ; those called morphogens elicit many responses in target cells depending on their level of expression (concentration).

One developmental signaling pathway is initiated by the secreted protein called sonic hedgehog (SHH) that sets off a chain of events resulting in activation and repression of target cells by transcription factors in the GLI family. Perturbations (disturbances) in the regulation of the Shh–Patched–Gli (SHH–PTCH–GLI) signaling pathway lead to several human diseases, including some cancers and birth defects.

SHH is expressed in the notochord, the floor plate of the neural tube, the brain, and other regions, such as the zone of polarizing activity of the developing limbs and the gut. Sporadic and inherited mutations in the human SHH gene leads to holoprosencephaly (see Chapter 17 , Fig. 17.40 ), a midline defect of variable severity involving abnormal CNS septation, facial clefting, single central incisor, hypotelorism, or a single cyclopic eye (see Chapter 18 , Fig. 18.6 ). The SHH protein needs to be processed to an active form and is modified by the addition of a cholesterol moiety. Defects in cholesterol biosynthesis, such as in the autosomal recessive disorder Smith–Lemli–Opitz syndrome (cognitive deficiency, small stature, ptosis, and male genital defects), share many features, particularly brain and limb defects reminiscent of SHH-related diseases. This suggests that signaling through SHH may play a key role in several genetic disorders.

Three transcriptional factors encoded by GLI genes are in the SHH–PTCH–GLI pathway. Mutations in the GLI3 gene have been implicated in several autosomal dominant disorders, including Greig cephalopolysyndactyly syndrome (deletions or point mutations); Pallister-Hall syndrome with hypothalamic hamartomas, central or postaxial polydactyly, and other defects of the face, brain, and limbs (frameshift or nonsense mutations); simple familial postaxial polydactyly type A and B; and preaxial polydactyly type IV (nonsense, missense, and frameshift mutations).

A comprehensive, authoritative, and daily updated listing of all known human genetic disorders and gene loci can be found at the Online Mendelian Inheritance in Man (OMIM) website ( www.ncbi.nlm.nih.gov/omim ). The OMIM is authored and edited by the McKusick-Nathans Institute for Genetic Medicine at Johns Hopkins University.

Principles of Teratogenesis

When considering the possible teratogenicity of a drug or chemical, three important principles must be considered:

• Critical periods of development

• Dose of the drug or chemical

• Genotype (genetic constitution) of the embryo

Critical Periods of Human Development

The embryo's stage of development when it encounters a drug or virus determines its susceptibility to the teratogen (see Fig. 20.1 ). The most critical period of development is when cell division, cell differentiation, and morphogenesis are at their peak. Table 20.7 indicates the relative frequencies of birth defects for certain organs.

The critical period for brain development is from 3 to 16 weeks, but development may be disrupted after this because the brain is differentiating and growing rapidly at birth. Teratogens may produce cognitive deficiency during the embryonic and fetal periods (see Fig. 20.1 ).

Tooth development continues long after birth (see Chapter 19 , Table 19.1 ). Development of permanent teeth may be disrupted by tetracyclines from 14 weeks of fetal life up to 8 years after birth (see Chapter 19 , Fig. 19.20 E ). The skeletal system also has a prolonged critical period of development extending into childhood, and the growth of skeletal tissues provides a good gauge of general growth.

Environmental disturbances during the first 2 weeks after fertilization may interfere with cleavage of the zygote and implantation of the blastocyst and may cause early death and spontaneous abortion of an embryo. However, disturbances during the first 2 weeks are not known to cause birth defects (see Fig. 20.1 ). Teratogens acting during the first 2 weeks kill the embryo, or their disruptive effects are compensated for by powerful regulatory properties of the early embryo. Most development during the first 4 weeks is concerned with the formation of extraembryonic structures such as the amnion, umbilical vesicle, and chorionic sac (see Chapter 3 , Fig. 3.8 and Chapter 5 , Figs. 5.1 and 5.18 ).

Development of the embryo is most easily disrupted when the tissues and organs are forming ( Fig. 20.18 ; see Fig. 20.1 ). During this organogenetic period (4 to 8 weeks; see Chapter 1 , Fig. 1.1 ), teratogens may induce major birth defects. Physiologic defects such as minor morphologic defects of the external ears and functional disturbances such as cognitive deficiency are likely to result from disruption of development during the fetal period (ninth week to birth).

Each tissue, organ, and system of an embryo has a critical period during which its development may be disrupted (see Fig. 20.1 ). The type of birth defect produced depends on which parts, tissues, and organs are most susceptible at the time the teratogen is encountered. Several examples show how teratogens may affect different organ systems that are developing at the same time:

• High levels of ionizing radiation produce defects of the CNS (brain and spinal cord) and eyes.

• Rubella virus infection causes eye defects (glaucoma and cataracts), deafness, and cardiac defects.

• Drugs such as thalidomide induce limb defects and other anomalies such as cardiac and kidney defects.

Early in the critical period of limb development, thalidomide causes severe defects such as meromelia, which is an absence of parts of the upper and lower limbs (see Fig. 20.2 ). Later in the sensitive period, thalidomide causes mild to moderate limb defects such as hypoplasia of the radius and ulna.

Embryologic timetables (see Fig. 20.1 ) are helpful when considering the cause of a human birth defect, but it is wrong to assume that defects always result from a single event occurring during the critical period or that it is possible to determine from these tables the exact day the defect was produced. It can only be stated that the teratogen would have had to disrupt development before the end of the critical period for the tissue, part, or organ.

Genotype of Embryo

Numerous examples in experimental animals and several suspected cases in humans show that genetic differences alter responses to a teratogen. Phenytoin , for example, is a well-known human teratogen (see Table 20.1 ). Between 5% and 10% of embryos exposed to this anticonvulsant medication develop the fetal hydantoin syndrome ( Fig. 20.19 ). Approximately one third of exposed embryos, however, have only some of the birth defects, and more than one half of the embryos are unaffected. It appears that the genotype of the embryo determines whether a teratogenic agent will disrupt its development.

Human Teratogens

Awareness that certain agents can disrupt prenatal development offers the opportunity to prevent some birth defects. For example, if women are aware of the harmful effects of drugs, environmental chemicals, and some viruses, most will not expose their embryos to these teratogenic agents.

The objective of teratogenicity testing of drugs, chemicals, and other agents is to identify risk factors that may cause malformations during human development and alert pregnant women and their caregivers about the dangers to their embryos or fetuses.

Drugs as Teratogens

The teratogenicity of drugs varies considerably. Some teratogens (e.g., thalidomide) cause severe disruption of development if administered during the organogenetic period from the fourth to eighth weeks ( Figs. 20.1 and 20.2 ). Other teratogens cause cognitive deficiency, growth restriction, and other defects if used excessively throughout development. In the case of alcohol, there is no safe amount during pregnancy.

The use of prescription and nonprescription drugs during pregnancy is surprisingly high. Between 40% and 90% of women consume at least one nonprescription drug during pregnancy. Several studies have indicated that some pregnant women take an average of four drugs, excluding nutritional supplements, and that approximately one half of these women take them during the highly sensitive period (see Fig. 20.1 ). Another report that was based on a database of prescribed drugs showed that pregnant women might be prescribed as many as 10 drugs. Despite this, less than 2% of birth defects are caused by drugs and chemicals. Only a few drugs have been positively implicated as human teratogenic agents (see Table 20.1 ); however, new agents continue to be identified. Women should avoid all medications during the first trimester unless there is a strong medical reason for their use and then only if the drugs are recognized as reasonably safe for the embryo. Even though well-controlled studies of certain drugs (e.g., marijuana) have failed to demonstrate a teratogenic risk to embryos, they affect the development of the embryo (e.g., fetal decreased growth, birth weight).

Cigarette Smoking

Maternal smoking during pregnancy is a well-established cause of intrauterine growth restriction (IUGR) . Low birth weight (<2000 g) is the chief predictor of infant death. Among heavy cigarette smokers, premature delivery is twice as frequent compared with mothers who do not smoke (see Chapter 6 , Fig. 6.11 ).

In a population-based case-control study, there was a modest increase in the incidence of conotruncal and atrioventricular septal heart defects associated with maternal smoking in the first trimester. There is some evidence that maternal smoking may cause urinary tract anomalies, behavioral problems, and IUGR.

Nicotine constricts uterine blood vessels, decreasing uterine blood flow and lowering the supply of oxygen and nutrients available to the embryo or fetus from the maternal blood in the intervillous space of the placenta (see Chapter 7 , Figs. 7.5 and 7.7 ). The resulting deficiency impairs cell growth and may have an adverse effect on cognitive development. High levels of carboxyhemoglobin resulting from cigarette smoking appear in the maternal and fetal blood and may alter the capacity of the blood to transport oxygen. Chronic fetal hypoxia (low oxygen levels) may occur and affect fetal growth and development. Maternal smoking is also associated with smaller brain volumes in preterm infants.

Alcohol

Moderate and high levels of alcohol intake during early pregnancy may alter the growth and morphogenesis of the embryo or fetus. Alcoholism affects 1% to 2% of women of childbearing age. Maternal alcohol abuse is thought to be the most common cause of cognitive deficiency. Neonates born to chronic alcoholic mothers exhibit a specific pattern of defects, including prenatal and postnatal growth deficiency, cognitive deficiency, and other defects ( Fig. 20.20 , and see Table 20.1 ).

Microcephaly ( small neurocranium ; see Chapter 17 , Fig. 17.36 ), short palpebral fissures, epicanthal folds, maxillary hypoplasia, short nose, thin upper lip, abnormal palmar creases, joint defects, growth retardation, congenital heart disease , and scores of other birth defects and comorbidities are present in these infants. The specific pattern of defects in affected infants and children with the sentinel facial features, growth impairment, and cognitive disability is called fetal alcohol syndrome (FAS), with a prevalence of 1 to 2 infants per 1000 live births (see Fig. 20.20 ).

The prevalence of FAS is related to the population studied. Clinical experience is often necessary to make an accurate diagnosis of FAS because the physical defects in affected children can be nonspecific. Nonetheless, the overall pattern of clinical features is unique but may vary from subtle to severe.

Moderate maternal alcohol consumption (1 to 2 oz of alcohol per day) can result in cognitive impairment and behavioral problems. The term fetal alcohol effects (FAEs) was introduced after recognition that many children exposed to alcohol in utero had no external dysmorphic features but had neurodevelopmental impairments.

The preferred term for the range of prenatal alcohol effects is fetal alcohol spectrum disorder (FASD) . The prevalence of FASD in the general population is 1% or higher. Because the susceptible period of brain development spans the major part of gestation (see Fig. 20.1 ), the safest and most prudent advice is total abstinence from alcohol during pregnancy .

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here