Developmental Disorders: Causes, Mechanisms, and Patterns

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Chapter 8

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).

Fig. 8.1 A, Chalk carving from New Ireland in the South Pacific showing dicephalic, dibrachic conjoined twins *(left).* Note also the “collar” beneath the heads, which is a representation of the malformation cystic hygroma colli *(right).* B, The bird-boy of Paré (about 1520) *(left).* Stillborn fetus with sirenomelia (fused legs) *(right).* Compare with the lower part of the bird-boy. (A *[left,]* From Brodsky I: *Med J Aust* 1:417-420, 1943; A *[right]* and B *[right]*, Courtesy of M. Barr, Ann Arbor, Mich.)

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.

Fig. 8.2 Phocomelia in all four limbs.
This fetus had not been exposed to thalidomide. (Courtesy of M. Barr, Ann Arbor, Mich.)

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).

Fig. 8.3 The increased incidence of Down syndrome with increasing maternal age (A) and achondroplasia and Apert’s syndrome with increasing paternal age (B). Apert’s syndrome (acrocephalosyndactyly) is characterized by a towering skull and laterally fused digits.

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.

Fig. 8.4 Frontal (A) and lateral (B) views of anencephaly. (Courtesy of M. Barr, Ann Arbor, Mich.)

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.

Fig. 8.5 Generalized susceptibility curve to teratogenic influences by a single organ.

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.

Fig. 8.6 Periods and degrees of susceptibility of embryonic organs to teratogens. (Adapted from Moore KL, Persaud TVN: *The developing human,* ed 5, Philadelphia, 1993, Saunders.)

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
Rubella virus	0-120+	Deafness
Thalidomide	21-40	Reduction defects of limbs
Androgenic steroids	Earlier than 90	Clitoral hypertrophy and labial fusion
Androgenic steroids	Later than 90	Clitoral hypertrophy only
Warfarin (Coumadin) anticoagulants	Earlier than 100	Nasal hypoplasia
Warfarin (Coumadin) anticoagulants	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
Tetracycline	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.

Patterns of Abnormal Development

Although isolated structural or biochemical defects are not rare, it is also common to find multiple abnormalities in the same individual. This can result for many reasons. One possibility is that a single teratogen acted on the primordia of several organs during susceptible periods of development. Another is that a genetic or chromosomal defect spanned genes affecting a variety of structures, or that a single metabolic defect affected different developing structures in different ways.

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.