Developmental Disorders: Causes, Mechanisms, and Patterns

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Developmental Disorders

Causes, Mechanisms, and Patterns

Congenital malformations have attracted attention since the dawn of human history. When seen in humans or animals, malformations were often interpreted as omens of good or evil. Because of the great significance attached to congenital malformations, they were frequently represented in folk art as sculptures or paintings. As far back as the classical Greek period, people speculated that maternal impressions during pregnancy (e.g., being frightened by an animal) caused development to go awry. In other cultures, women who gave birth to malformed infants were assumed to have had dealings with the devil or other evil spirits.

Early representations of some malformed infants are remarkable in their anatomical accuracy, and it is often possible to diagnose specific conditions or syndromes from the ancient art (Fig. 8.1A). By the Middle Ages, however, representations of malformations were much more imaginative, with hybrids of humans and other animals often represented (Fig. 8.1B).

Among the first applications of scientific thought to the problem of congenital malformations were those of the sixteenth-century French surgeon Ambrose Paré, who suggested a role for hereditary factors and mechanical influences, such as intrauterine compression, in the genesis of birth defects. Less than a century later, William Harvey, who is also credited with first describing the circulation of blood, elaborated the concept of developmental arrest and further refined thinking on mechanical causes of birth defects.

In the early nineteenth century, Etienne Geoffroy de St. Hilaire coined the term teratology, which literally means “the study of monsters,” as a descriptor for the newly emerging study of congenital malformations. Late in the nineteenth century, scientific study of teratology was put on a firm foundation with the publication of several encyclopedic treatises that exhaustively covered anatomical aspects of recognized congenital malformations.

After the flowering of experimental embryology and genetics in the early twentieth century, laboratory researchers began to produce specific recognizable congenital anomalies by means of defined experimental genetic or laboratory manipulations on laboratory animals. This work led to the demystification of congenital anomalies and to a search for rational scientific explanations for birth defects. Nevertheless, old beliefs are tenacious, and even today patients may adhere to traditional beliefs.

The first of two major milestones in human teratology occurred in 1941, when Gregg in Australia recognized that the rubella virus was a cause of a recognizable syndrome of abnormal development, consisting of defects in the eyes, ears, and heart. About 20 years later, the effects of thalidomide sensitized the medical community to the potential danger of certain drugs and other environmental teratogens (agents that produce birth defects) to the developing embryo.

Thalidomide is a very effective sedative that was widely used in West Germany, Australia, and other countries during the late 1950s. Soon, physicians began to see infants born with extremely rare birth defects. One example is phocomelia (which means “seal limb”), a condition in which the hands and feet seem to arise almost directly from the shoulder and hip (Fig. 8.2). Another is amelia, in which a limb is entirely missing. Thalidomide was identified as the certain cause after some careful epidemiological detective work involving the collection of individual case reports and sorting of the drugs taken by mothers during the early period of their pregnancies. Thalidomide, which is an inhibitor of tumor necrosis factor-α, is still a drug of choice in the treatment of leprosy and multiple myeloma. With the intense investigations that followed the thalidomide disaster, modern teratology came of age. Despite much effort, however, the causes of most congenital malformations are still unknown.

General Principles

According to most studies, approximately 2% to 3% of all living newborns show at least one recognizable congenital malformation. This percentage is doubled when one considers anomalies diagnosed in children during the first few years after birth. With the decline in infant mortality caused by infectious diseases and nutritional problems, congenital malformations now rank high among the causes of infant mortality (currently >20%), and increasing percentages (≤30%) of infants admitted to neonatology or pediatric units come as a result of various forms of genetic diseases or congenital defects.

Congenital defects range from enzyme deficiencies caused by single nucleotide substitutions in the DNA molecule to very complex associations of gross anatomical abnormalities. Although medical embryology textbooks traditionally cover principally structural defects—congenital malformations—there is a continuum between purely biochemical abnormalities and defects that are manifested as abnormal structures. This continuum includes defects that constitute abnormal structure, function, metabolism, and behavior.

Birth defects present themselves in a variety of forms and associations, ranging from simple abnormalities of a single structure to often grotesque deformities that may affect an entire body region. Some of the common classes of malformations are listed in Table 8.1.

Table 8.1

Types of Abnormal Development

Abnormalities of Individual Structures
Malformation A structural defect of part of or an entire organ or larger part of a body region that is caused by an abnormal process intrinsic to its development (e.g., coloboma) (see p. 285)
Disruption A defect in an organ or body part caused by process that interferes with an originally normal developmental process (e.g., thalidomide-induced phocomelia) (see p. 149)
Deformation A structural abnormality caused by mechanical forces (e.g., amniotic band constriction) (see Fig. 8.16)
Dysplasia An abnormality of a tissue due to an abnormal intrinsic developmental process (e.g., ectodermal dysplasia) (see p. 150)
Defects Involving More Than One Structure
Sequence A pattern of multiple malformations stemming from a disturbance of a prior developmental process or mechanical factor (e.g., Potter sequence) (see p. 384)
Syndrome A group of malformations of different structures due to a single primary cause, but acting through multiple developmental pathways (e.g., trisomy 13 syndrome) (see Fig. 8.10)
Association A group of anomalies seen in more than one individual that cannot yet be attributed to a definitive cause


Based on Spranger J and others: J Pediatr 100:160-165, 1982.

The genesis of congenital defects can be viewed as an interaction between the genetic endowment of the embryo and the environment in which it develops. The basic information is encoded in the genes, but as the genetic instructions unfold, the developing structures or organs are subjected to microenvironmental or macroenvironmental influences that either are compatible with or interfere with normal development. In the case of genetically based malformations or anomalies based on chromosomal aberrations, the defect is intrinsic and is commonly expressed even in a normal environment. Purely environmental causes can interfere with embryological processes in the face of a normal genotype. In other cases, environment and genetics interact. Penetrance (the degree of manifestation) of an abnormal gene or expression of one component of a genetically multifactorial cascade can sometimes be profoundly affected by environmental conditions.

Studies on mice have shown that defective function of many genes leads to some sort of developmental disturbance. Some of these defects are purely mutational, residing in the structure of the DNA itself, whereas others result from interference in transcription or translation or from regulatory elements of the gene.

Several factors are associated with various types of congenital malformations. At present, they are understood more at the level of statistical associations than as points of interference with specific developmental controls, but they are important clues to why development can go wrong. Among the factors associated with increased incidences of congenital malformations are (1) parental age, (2) season of the year, (3) country of residence, (4) race, and (5) familial tendencies.

Well-known correlations exist between parental age and the incidence of certain malformations. A classic correlation is the increased incidence of Down syndrome (Fig. 8.3; see Fig. 8.9) in children born to women older than 35 years of age. Other conditions are related to paternal age (see Fig. 8.3).

Some types of anomalies have a higher incidence among infants born at certain seasons of the year. Anencephaly (Fig. 8.4) occurs more frequently in January. Recognizing that the primary factors leading to anencephaly occur during the first month of embryonic life, researchers must seek the potential environmental causes that are more prevalent in April. Anencephaly has been shown to be highly correlated with maternal folic acid deficiency. The high incidence of this anomaly in pregnancies beginning in the early spring may relate to nutritional deficiencies of mothers during the late winter months. Folic acid supplementation in the diet of women of childbearing age significantly reduces the incidence of neural tube defects, such as anencephaly.

The relationship between the country of residence and an increased incidence of specific malformations can be related to various factors, including racial tendencies, local environmental factors, and even governmental policies. A classic example of the last is the incidence of severely malformed infants as a result of exposure to thalidomide. These cases were concentrated in West Germany and Australia because the drug was commonly sold in these locations. Because thalidomide was not approved by the Food and Drug Administration, the United States was spared from this epidemic of birth defects. Another classic example of the influence of country as a factor in the incidence of malformations is seen in neural tube defects (Table 8.2). The reason neural tube defects (especially anencephaly) were historically so common in Ireland has been the topic of much speculation. In light of the recognition of the importance of folic acid in the prevention of neural tube defects, it is possible that the high incidence of anencephaly in Ireland resulted from poor nutrition in pregnant women during the winter. A greater than threefold decrease in the incidence of neural tube defects in Ireland from 1980 to 1994 may be related to both better nutrition and folic acid supplementation by a certain percentage of pregnant women.

Table 8.2

Incidence of Neural Tube Defects

Site Incidence*
India 0.6
Ireland 10
United States 1
Worldwide 2.6


*Per 1000 live births.

The present incidence in Ireland is much decreased.

Race is a factor in many congenital malformations and a variety of diseases. In humans and mice, there are racial differences in the incidence of cleft palate. The incidence of cleft palate among whites is twice as high as it is among blacks and twice as high among Korean, Chinese, and Japanese persons as among whites.

Many malformations, particularly those with a genetic basis, are found more frequently within certain families, especially if there is any degree of consanguinity in the marriages over the generations. A good example is the increased occurrence of extra digits among some families within the Amish community in the United States.

Periods of Susceptibility to Abnormal Development

At certain critical periods during pregnancy, embryos are more susceptible to agents or factors causing abnormal development than at other times. The results of many investigations have allowed the following generalization: Insults to the embryo during the first 3 weeks of embryogenesis (the early period before organogenesis begins) are unlikely to result in defective development because they either kill the embryo or are compensated for by the powerful regulatory properties of the early embryo. The period of maximal susceptibility to abnormal development occurs between weeks 3 and 8, which is the period when most of the major organs and body regions are first being established.

Major structural anomalies are unlikely to occur after the eighth week of pregnancy because, by this point, most organs have become well established. Anomalies arising from the third to the ninth month of pregnancy tend to be functional (e.g., mental retardation) or involve disturbances in the growth of already formed body parts. Such a simplified view of susceptible periods does not take into account, however, the possibility that a teratogen or some other harmful influence may be applied at an early stage of development, but not be expressed as a developmental disturbance until later during embryogenesis. Certain other influences (e.g., intrauterine diseases, toxins) may result in the destruction of all or parts of structures that have already been formed.

Typically, a developing organ has a curve of susceptibility to teratogenic influences similar to that illustrated in Figure 8.5. Before the critical period, exposure to a known teratogen has little influence on development. During the first days of the critical period, the susceptibility, measured as incidence or severity of malformation, increases sharply and then declines over a much longer period.

Different organs have different periods of susceptibility during embryogenesis (Fig. 8.6). Organs that form the earliest (e.g., heart) tend to be sensitive to the effects of teratogens earlier than organs that form later (e.g., external genitalia). Some very complex organs, especially the brain and major sense organs, show prolonged periods of high susceptibility to disruption of normal development.

Not all teratogenic influences act in the same developmental periods (Table 8.3). Some influences cause anomalies if the embryo is exposed to them early in development, but they are innocuous at later periods of pregnancy. Others affect only later developmental periods. A good example of the former is thalidomide, which has a very narrow and well-defined danger zone during the embryonic period (4 to 6 weeks). In contrast, tetracycline, which stains bony structures and teeth, exerts its effects after hard skeletal structures in the fetus have formed.

Table 8.3

Developmental Times at Which Various Human Teratogens Exert Their Effects

Teratogens Critical Periods (Gestational Days) Common Malformations
Rubella virus 0-60 Cataract or heart malformations
0-120+ Deafness
Thalidomide 21-40 Reduction defects of limbs
Androgenic steroids Earlier than 90 Clitoral hypertrophy and labial fusion
Later than 90 Clitoral hypertrophy only
Warfarin (Coumadin) anticoagulants Earlier than 100 Nasal hypoplasia
Later than 100 Possible mental retardation
Radioiodine therapy Later than 65-70 Fetal thyroid deficiency
Tetracycline Later than 120 Staining of dental enamel in primary teeth
Later than 250 Staining of crowns of permanent teeth


Adapted from Persaud TVN, Chudley AE, Skalko RG, eds: Basic concepts in teratology, New York, 1985, Liss.

Causes of Malformations

Despite considerable research since the 1960s, the cause of at least 50% of human congenital malformations remains unknown (Fig. 8.7). Roughly 18% of malformations can be attributed to genetic causes (chromosomal defects or mutations based on mendelian genetics), and 7% of malformations are caused by environmental factors, such as physical or chemical teratogens. Of all malformations, 25% are multifactorial, for example, caused by environmental factors acting on genetic susceptibility.

The high percentage of unknown causes is the result of having to work retrospectively to identify the origin of a malformation. Many of these causes are likely to result from some environmental factor influencing the expression of a developmentally critical gene.

Genetic Factors

Genetically based malformations can be caused by abnormalities of chromosomal division or by mutations of genes. Chromosomal abnormalities are usually classified as structural or numerical errors. These arise during cell division, especially meiosis. Numerical errors of chromosomes result in aneuploidy, defined as a total number of chromosomes other than the normal 46.

Abnormal Chromosome Numbers

Monosomy and Trisomy

Monosomy (the lack of one member of a chromosome pair) and trisomy (a triplet instead of the normal chromosome pair) are typically the result of nondisjunction during meiosis (see Fig. 1.7). When this happens, one gamete shows monosomy, and the other shows trisomy of the same chromosome.

In most cases, embryos with monosomy of the autosomes or sex chromosomes are not viable. Some individuals with monosomy of the sex chromosomes (45XO genotype) can survive, however (Fig. 8.8). Such individuals, who are said to have Turner’s syndrome, exhibit a female phenotype, but the gonads are sterile.

Three autosomal trisomies produce infants with characteristic associations of anomalies. The best known is trisomy 21, also called Down syndrome. Individuals with Down syndrome are typically mentally retarded and have a characteristic broad face with a flat nasal bridge, wide-set eyes, and prominent epicanthic folds. The hands are also broad, and the palmar surface is marked by a characteristic transverse simian crease (Fig. 8.9). Heart defects, especially atrial and ventricular septal defects, are common, with an incidence approaching 50%. Duodenal atresia and other intestinal anomalies are also seen in patients with Down syndrome. Individuals with Down syndrome are prone to the early appearance of Alzheimer’s disease and typically have a shortened life span.

Trisomies of chromosomes 13 and 18 result in severely malformed fetuses, many of which do not survive to birth. Infants with trisomy 13 and trisomy 18 show severe mental retardation and other defects of the central nervous system. Cleft lip and cleft palate are common. Polydactyly is often seen in trisomy 13, and infants with both syndromes exhibit other anomalies of the extremities, such as “rocker bottom feet,” meaning a rounding under and protrusion of the heels (Fig. 8.10). Most infants born with trisomy 13 or trisomy 18 die within the first 1 or 2 months after birth.

Abnormal numbers of the sex chromosomes are relatively common and can be detected by examination of the sex chromatin (X chromosome) or the fluorescence reactions of the Y chromosomes. Table 8.4 summarizes some of the various types of deletions and duplications of the sex chromosomes.

Table 8.4

Variations in Numbers of Sex Chromosomes

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