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.

Fig. 8.7 Major causes of congenital malformations. (Data from Persaud TVN, Chudley AE, Skalko RG, eds: *Basic concepts in teratology,* New York, 1985, Liss.)

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

Polyploidy

Polyploidy is the condition in which the chromosomal number is a higher multiple than 2 of the haploid number (23) of chromosomes. In most cases, polyploid embryos abort spontaneously early in pregnancy. High percentages of spontaneously aborted fetuses show major chromosomal abnormalities. Polyploidy, especially triploidy, is likely to be caused by either the fertilization of an egg by more than one sperm or the lack of separation of a polar body during meiosis.

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.

Fig. 8.8 Woman with Turner’s syndrome.
Note the short stature, webbed neck, and infantile sexual characteristics. (From Connor J, Ferguson-Smith M: *Essential medical genetics,* ed 2, Oxford, 1987, Blackwell Scientific.)

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.

Fig. 8.9 A, Profile of a child with Down syndrome. Note the flat profile, protruding tongue, saddle-shaped bridge of nose, and low-set ears. B, Hand of an infant with Down syndrome shows the prominent simian crease that crosses the entire palm. (A, From Garver K, Marchese S: *Genetic counseling for clinicians,* Chicago, 1986, Mosby; B, Courtesy of M. Barr, Ann Arbor, Mich.)

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.

Fig. 8.10 A, Front and lateral views of the head of a 34-week fetus with trisomy 13. This fetus shows pronounced cebocephaly with a keel-shaped head, a flattened nose, abnormal ears, and a reduction of forebrain and upper facial structures. B, Rocker-bottom feet from a fetus with trisomy 18. Note the prominent heels and convex profile of the soles of the feet. C, Pronounced radial deviation of hands (club hands) of the same infant as in B. (Courtesy of M. Barr, Ann Arbor, Mich.)

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

Sex Chromosome Complement	Incidence	Phenotype	Clinical Factors
XO	1 : 3000	Immature female	Turner’s syndrome: short stature, webbed neck, high and arched palate (see Fig. 8-8)
XX		Female	Normal
XY		Male	Normal
XXY	1 : 1000	Male	Klinefelter’s syndrome: small testes, infertility, often tall with long limbs
XYY	1 : 1000	Male	Tall, normal appearance; reputed difficulty with impulsive behavior
XXX	1 : 1000	Female	Normal appearance, mental retardation (up to one third of cases), fertile (in many cases)

Abnormal Chromosome Structure

Various abnormalities of chromosome structure can give rise to malformations in development. Some chromosomal abnormalities result from chromosome breakage induced by environmental factors such as radiation and certain chemical teratogens. This type of structural error is usually unique to a given individual and is not transmitted to succeeding generations.

Other types of structural abnormalities of chromosomes are generated during meiosis and, if present in the germ cells, can be inherited. Common types of errors in chromosome structure are reciprocal translocations, isochromosome formation, and deletions and duplications (Fig. 8.11). One well-defined congenital malformation resulting from a deletion in the short arm of chromosome 5 is the cri du chat syndrome. Infants with this syndrome are severely mentally retarded, have microcephaly, and make a cry that sounds like the mewing of a cat.

Fig. 8.11 Different types of structural errors of chromosomes.

Genetic Mutations

Many genetic mutations are expressed as morphological abnormalities. These mutations can be of dominant or recessive genes of either the autosomes or the sex chromosomes. For some of these conditions (e.g., hemophilia, Lesch-Nyhan syndrome, muscular dystrophy, cystic fibrosis), the molecular or biochemical lesion has been identified, but the manner in which these defects are translated into abnormal development is unclear. Many of these conditions are discussed extensively in textbooks of human genetics, and only representative examples are listed here (Table 8.5).

Table 8.5

Genetic Mutations Leading to Abnormal Development

Condition	Characteristics
Autosomal Dominant
Achondroplasia	Dwarfism caused mainly by shortening of limbs
Aniridia	Absence of iris (usually not complete)
Crouzon’s syndrome (craniofacial dysostosis) (see Fig. 9.30)	Premature closure of certain cranial sutures leading to flat face and towering skull
Neurofibromatosis	Multiple neural crest–derived tumors on skin, abnormal pigment areas on skin
Polycystic kidney disease (adult onset, type III)	Numerous cysts in kidneys
Autosomal Recessive
Albinism	Absence of pigmentation
Polycystic kidney disease (perinatal type I) (see Fig. 16.17)	Numerous cysts in kidneys
Congenital phocomelia syndrome (see Fig. 8.2)	Limb deformities
X-Linked Recessive
Hemophilia	Defective blood clotting
Hydrocephalus (see Fig. 11.38)	Enlargement of cranium
Ichthyosis	Scaly skin
Testicular feminization syndrome	Female phenotype caused by inability to respond to testosterone

Environmental Factors

Various environmental factors are linked with birth defects. These influences range from chemical teratogens and hormones to maternal infections and nutritional factors. Although the list of suspected teratogenic factors is long, relatively few are unquestionably teratogenic in humans.

Maternal Infections

Since the recognition in 1941 that rubella was the cause of a spectrum of developmental anomalies, several other maternal diseases have been implicated as direct causes of birth defects. With infectious diseases, it is important to distinguish diseases that cause malformations by interfering with early stages in the development of organs and structures from diseases that interfere by destroying structures already formed. The same pathogenic organism can cause lesions by interference with embryonic processes or by destruction of differentiated tissues, depending on when the organism attacks the embryo.

Most infectious diseases that cause birth defects are viral, with toxoplasmosis (caused by the protozoan Toxoplasma gondii) and syphilis (caused by the spirochete Treponema pallidum) being notable exceptions. (A summary of the infectious diseases known to cause birth defects in humans is given in Table 8.6.)

Table 8.6

Infectious Diseases That Can Cause Birth Defects

Infectious Agent	Disease	Congenital Defects
Viruses
Rubella virus	German measles	Cataracts, deafness, cardiovascular defects, fetal growth retardation
Cytomegalovirus	Cytomegalic inclusion disease	Microcephaly, microphthalmia, cerebral calcification, intrauterine growth retardation
Spirochetes
Treponema pallidum (syphilis)	Syphilis	Dental anomalies, deafness, mental retardation, skin and bone lesions, meningitis
Protozoa
Toxoplasma gondii	Toxoplasmosis	Microcephaly, hydrocephaly, cerebral calcification, microphthalmia, mental retardation, prematurity

The time of infection is very important in relation to the types of effects on the embryo. Rubella causes a high percentage of malformations during the first trimester, whereas cytomegalovirus infections usually kill the embryo during the first trimester. The agents of syphilis and toxoplasmosis cross the placental barrier during the fetal period and, to a large extent, cause malformations by destroying existing tissues.

Chemical Teratogens

Many substances are known to be teratogenic in animals or are associated with birth defects in humans, but convincing evidence that links the substance directly to congenital malformations in humans exists for only a relatively small number (Table 8.7). Testing drugs for teratogenicity is difficult because what can cause a high incidence of severe defects in animal fetuses (e.g., cortisone and cleft palate in mice) may not cause malformations in other species of animals or in humans. Conversely, the classic teratogen thalidomide is highly teratogenic in humans, rabbits, and some primates, but not in commonly used laboratory rodents.

Table 8.7

Chemical Teratogens in Humans

Agent	Effects
Alcohol	Growth and mental retardation, microcephaly, various malformations of face and trunk
Androgens	Masculinization of females, accelerated genital development in males
Anticoagulants (warfarin, dicumarol)	Skeletal abnormalities; broad hands with short fingers; nasal hypoplasia; anomalies of eye, neck, central nervous system
Antithyroid drugs (e.g., propylthiouracil, iodide)	Fetal goiter, hypothyroidism
Chemotherapeutic agents (methotrexate, aminopterin)	Variety of major anomalies throughout body
Diethylstilbestrol	Cervical and uterine abnormalities
Lithium	Heart anomalies
Organic mercury	Mental retardation, cerebral atrophy, spasticity, blindness
Phenytoin (Dilantin)	Mental retardation, poor growth, microcephaly, dysmorphic face, hypoplasia of digits and nails
Isotretinoin (Accutane)	Craniofacial defects, cleft palate, ear and eye deformities, nervous system defects
Streptomycin	Hearing loss, auditory nerve damage
Tetracycline	Hypoplasia and staining of tooth enamel, staining of bones
Thalidomide	Limb defects, ear defects, cardiovascular anomalies
Trimethadione and paramethadione	Cleft lip and palate, microcephaly, eye defects, cardiac defects, mental retardation
Valproic acid	Neural tube defects

Alcohol

Accumulated evidence now leaves little doubt that maternal consumption of alcohol during pregnancy can lead to a well-defined constellation of developmental abnormalities that includes poor postnatal growth rate, microcephaly, mental retardation, heart defects, and hypoplasia of facial structures (Fig. 8.14). This constellation of abnormalities is now popularly known as fetal alcohol syndrome, and estimates suggest that some form of fetal alcohol syndrome may affect as many as 1% to 5% of all live births. Ingestion of 3 oz of alcohol in a day during the first 4 weeks of pregnancy can lead to extremely severe malformations of the holoprosencephaly type (see p. 309).

Exposure to alcohol later in pregnancy is less likely to cause major anatomical defects in the fetus, but because of the complex course of physiological maturation in the brain throughout pregnancy, more subtle behavioral defects can result. Nevertheless, there are often striking differences from normal in the size and shape of the corpus callosum, the main connecting link between the right and left sides of the brain, and in the cerebellum, which may be hypoplastic. Much of the abnormal development of the face and forebrain can be attributed to the death of cells in the anterior neural ridge (see Fig. 6.4B), which serves as a signaling center in the early embryo. Although the intelligence quotient (IQ) of an individual with fetal alcohol syndrome may be normal, such individuals may show deficits in recognition of the consequences of actions or in planning into the future.

Retinoic Acid (Vitamin A)

Derivatives of retinoic acid are used in the treatment of acne, but investigators have established that retinoic acid acts as a potent teratogen when it is taken orally. Retinoic acid can produce a wide spectrum of defects, most of which are related to derivatives of the cranial neural crest (see p. 259). These involve a variety of facial structures, the outflow tract of the heart, and the thymus (Fig. 8.15).

Fig. 8.15 Etretinate embryopathy.
Among multiple facial anomalies, this infant had a highly deformed ear. (From the Robert J. Gorlin collection, Division of Oral and Maxillofacial Pathology, University of Minnesota Dental School, courtesy of Dr. Ioannis Koutlas.)

Through a complex sequence of cytoplasmic binding proteins and nuclear receptors (see Fig. 4.18), retinoic acid affects Hox genes, especially genes expressed in the cranial and pharyngeal region (see Fig. 11.12), with resulting alterations of the anterior rhombomeres and the neural crest cells derived from them. As discussed later, neural crest cells emanating from rhombomeres are instrumental in patterning many structures of the face and neck and contribute to the developing heart and thymus, hence the pattern of retinoic acid–induced defects previously outlined. In view of the increasing recognition of the important role of retinoic acid or its metabolites in pattern formation during early development, extreme caution is recommended when vitamin A is used in doses greater than those needed for basic nutritional requirements.

Antibiotics

The use of two antibiotics during pregnancy is associated with birth defects. Streptomycin in high doses can cause inner ear deafness. Tetracycline given to the mother during late pregnancy crosses the placental barrier and seeks sites of active calcification in the teeth and bones of the fetus. Tetracycline deposits cause a yellowish discoloration of teeth and bones and, in high doses, can interfere with enamel formation.

Other Drugs

Numerous other drugs, such as the anticoagulant warfarin, are known to be teratogenic, and other agents are strongly suspected. Firm proof of a drug’s teratogenicity in humans is not easy to obtain, however. Several drugs, such as Agent Orange and some of the social drugs (e.g., lysergic acid diethylamide [LSD], marijuana), have often been claimed to cause birth defects, but the evidence to date is not entirely convincing. Several studies have shown a variety of complications in pregnancy resulting from the use of cocaine, which can readily cross the placental barrier. In addition to structural malformations in organs such as the brain, cocaine use has been linked to intrauterine growth retardation, premature labor, and spontaneous abortion, and postnatal behavioral disturbances, such as attention deficit.

Physical Factors

Ionizing Radiation

Ionizing radiation is a potent teratogen, and the response is both dependent on the dose and related to the stage at which the embryo is irradiated. In addition to numerous animal studies, there is direct human experience based on survivors of the Japanese atomic bomb blasts and pregnant women who were given large doses of radiation (up to several thousand rads) for therapeutic reasons. There is no evidence that doses of radiation at diagnostic levels (only a few millirads) pose a significant threat to the embryo. Nevertheless, because ionizing radiation can produce breaks in DNA and is known to cause mutations, it is prudent for a woman who is pregnant to avoid exposure to radiation if possible, although the dose in a diagnostic x-ray examination is so small that the risk is minimal.

Although ionizing radiation can cause a variety of anomalies in embryos (e.g., cleft palate, microcephaly, malformations of the viscera, limbs, and skeleton), defects of the central nervous system are very prominent in irradiated embryos. The spectrum runs from spina bifida to mental retardation.

Other Physical Factors

Numerous studies on the teratogenic effects of extremes of temperature and different concentrations of atmospheric gases have been conducted on experimental animals, but the evidence relating any of these factors to human malformations is still equivocal. One exception is the effect of excess concentrations of oxygen on premature infants. When this practice was common, retrolental fibroplasia developed in more than 10% of premature infants weighing less than 3 lb and in about 1% of premature infants weighing 3 to 5 lb. When this connection was recognized, the practice of maintaining high concentrations of oxygen in incubators ceased, and this problem is now of only historical interest.

Maternal Factors

Numerous maternal factors have been implicated in the genesis of congenital malformations. Maternal diabetes is frequently associated with high birth weight and with stillbirths. Structural anomalies occur several times more frequently in infants of diabetic mothers than in infants of mothers from the general population. Although there is a correlation between the duration and severity of the mother’s disease and the effects on the fetus, the specific cause of interference with development has not been identified.

In general, maternal nutrition does not seem to be a major factor in the production of anomalies (folic acid being a notable exception), but if the mother is severely deficient in iodine, the newborn is likely to show the symptoms of cretinism (growth retardation, mental retardation, short and broad hands, short fingers, dry skin, and difficulty breathing). There is now considerable evidence that heavy smoking by a pregnant woman leads to an increased risk of low birth weight and a low rate of growth after birth.

Mechanical Factors

Although mechanical factors have been implicated in the genesis of congenital malformations for centuries, only in more recent years has it been possible to relate specific malformations to mechanical causes. Many of the most common anomalies, such as clubfoot, congenital hip dislocations, and even certain deformations of the skull, can be attributed in large measure to abnormal intrauterine pressures imposed on the fetus. This situation can often be related to uterine malformations or a reduced amount of amniotic fluid (oligohydramnios).

Amniotic bands constricting digits or extremities of the fetus have been implicated as causes of intrauterine amputations (Fig. 8.16). These bands form as the result of tears to the extraembryonic membranes during pregnancy. Chorionic villus sampling results in a low percentage of transverse limb defects, but the mechanism underlying the defective limb development is not well understood.

Fig. 8.16 A, Digital amputations of the left hand presumably caused by amniotic bands. B, Amniotic bands involving the umbilical cord and limbs of a fetus. The *arrow* shows a constriction ring around the thigh. (A, Courtesy of M. Barr, Ann Arbor, Mich, B, from Wigglesworth JS, Singer DB: *Textbook of fetal and perinatal pathology,* 2 vols, Oxford, 1991, Blackwell Scientific.)

Developmental Disturbances Resulting in Malformations

Duplications and Reversal of Asymmetry

The classic example of duplication is identical twinning. Under normal circumstances, both members of the twin pair are completely normal, but rarely the duplication is incomplete, and conjoined twins result (see Figs. 3.15 and 3.16). Twins can be conjoined at almost any site and to any degree. With modern surgical techniques, it is now possible to separate members of some conjoined pairs. A type of conjoined twinning is the condition of parasitic twinning, in which one member of the pair is relatively normal, but the other is represented by a much smaller body, often consisting of just the torso and limbs, attached to an area such as the mouth or lower abdomen of the host twin (see Fig. 3.17). In numerous conjoined twins, one member of the pair has reversed asymmetry in relation to the other (see Fig. 3.16).

In rare instances (approximately 1 in 10,000 births), an otherwise normal individual is found to have a partial or complete reversal of the asymmetry of the internal organs, a condition called situs inversus (see Fig. 5.15). Molecular research on early embryonic stages (see Fig. 5.13) has begun to provide a mechanistic explanation for this condition.

Faulty Inductive Tissue Interactions

Absent or faulty induction early in development (e.g., induction of the central nervous system) is incompatible with life, but disturbances in later inductions can cause malformations. Absence of the lens (aphakia) or of a kidney (renal agenesis) can result from an absent or abnormal inductive interaction.

Absence of Normal Cell Death

Genetically or epigenetically (environmental influences imposed on the genetic background) controlled cell death is an important mechanism in sculpting many regions of the body. The absence of normal interdigital cell death has been implicated in syndactyly (webbed digits) (see Fig. 10.23A) and abnormal persistence of the tail (see Fig. 9.25A for normal tail). The latter phenomenon has sometimes been considered an example of atavism (the persistence of phylogenetically primitive structures).

Failure of Tube Formation

The formation of a tube from an epithelial sheet is a fundamental developmental mechanism. A classic case of failure of tube formation is seen in the spina bifida anomalies, which are based on the incomplete fusion of the neural tube (see Fig. 11.42). (Some of the possible mechanisms involved in normal formation of the neural tube are discussed in Chapter 11.)

Disturbances in Tissue Resorption

Some structures present in the early embryo must be resorbed for subsequent development to proceed normally. Examples are the membranes that cover the future oral and anal openings. These membranes are composed of opposing sheets of ectoderm and endoderm, but if mesodermal cells become interposed between the two and this tissue becomes vascularized, breakdown typically fails to occur. Anal atresia is a common anomaly of this type (see Fig. 15.19).

Failure of Migration

Migration is an important developmental phenomenon that occurs at the level of cells or entire organs. The neural crest is a classic example of massive migrations at the cellular level, and disturbances in migration can cause abnormalities in any of the structures for which the neural crest is a precursor (e.g., thymus, outflow tracts of the heart, adrenal medulla). At the organ level, the kidneys undertake a prominent migration into the abdominal cavity from their origin in the pelvic region, and the testes migrate from the abdominal cavity into the scrotum. Pelvic kidneys (see Fig. 16.15) and undescended testes (cryptorchidism) are relatively common.

Developmental Arrest

Early in the history of teratology, some malformations were recognized as the persistence of structures in a state that was normal at an earlier stage of development. Many of the patterns of cleft lip and cleft palate (see Figs. 14.16 and 14.17) are examples of developmental arrest, although it is incorrect to assume that development has been totally arrested since the sixth to eighth weeks of embryogenesis. Another example of the persistence of an earlier stage in development is a thyroglossal duct (see Fig. 14.45), in which persisting epithelial cells mark the path of the thyroid gland as it migrates from the base of the tongue to its normal position.

Destruction of Formed Structures

Many teratogenic diseases or chemicals produce malformations by the destruction of structures already present. If the structure is in the early primordial stage, any tissues to which the primordium would normally give rise are missing or malformed. Interference with the blood supply of a structure can cause unusual patterns of malformations. In the genesis of phocomelia (see Fig. 8.2), damage to proximal blood vessels could destroy the primordia of the proximal limb segments, but the cells of the distal limb bud that give rise to the hands or feet could be spared if the distal microvasculature of the limb bud remained intact.

Failure to Fuse or Merge

If two structures such as the palatal shelves fail to meet at the critical time, they are likely to remain separate. Similarly, the relative displacements of mesenchyme (merging) that are involved in the shaping of the lower jaw may not occur on schedule or in adequate amounts. This accounts for some malformations of the lower face.

Hypoplasia and Hyperplasia

The normal formation of most organs and complex structures requires a precise amount and distribution of cellular proliferation. If cellular proliferation in a forming organ is abnormal, the structure can become too small (hypoplastic) (see Fig. 16.12B) or too large (hyperplastic). Even minor growth disturbances can cause severe problems in complex regions such as the face. Occasionally, gigantism of a structure such as a digit (Fig. 8.17) or whole limb occurs. The mechanism underlying this excessive growth remains obscure.

Fig. 8.17 Gigantism (macrodactyly) of the great toe. (From the Robert J. Gorlin collection, Division of Oral and Maxillofacial Pathology, University of Minnesota Dental School, courtesy of Dr. Ioannis Koutlas.)

Receptor Defects

Some congenital malformations can be attributed to defects in specific receptor molecules. One of the earliest recognized is the testicular feminization syndrome, in which the lack of testosterone receptors results in the development of a typical female phenotype in a genetic male (see Fig. 9.13A).

Defective Fields

Proper morphogenesis of many regions of the body is under the control of poorly understood morphogenetic fields. These regions of the body are under the control of an overall developmental blueprint. Disturbances in the boundaries or overall controls of fields can sometimes give rise to massive anomalies. One example is the fusion of lower limb fields, which is probably associated with a larger defect in the field controlling the development of the caudal region of the body. This mermaidlike anomaly is called sirenomelia (see Fig. 8.1B), and it is an extreme example of what is called the caudal regression syndrome, resulting from abnormal T gene function (see p. 82).

Effects Secondary to Other Developmental Disturbances

Because so much of normal development involves the tight interlocking of individual processes or building on completed structures, it is not surprising that many malformations are secondary manifestations of other disturbed embryonic processes. There are numerous examples in craniofacial development. Some cases of cleft palate have been attributed to a widening of the cranial base so that the palatal shelves, which may have been normal, are unable to make midline contact.

The single or widely separated tubular probosces that appear in certain major facial anomalies, such as cyclopia (Fig. 8.18), are very difficult to explain unless it is understood that one of several primary defects, whether too much or too little tissue of the midface, prevented the two nasal primordia from joining in the midline. In the case of cyclopia, the primary defect is usually a deficiency of forebrain tissue that results from deficient sonic hedgehog signaling (see Clinical Correlation 14.1), and the facial defects are secondary to that.

Fig. 8.18 Cyclopia in a newborn.
Note the fleshy proboscis above the partially fused eye. (Courtesy of M. Barr, Ann Arbor, Mich.)

Germ Layer Defects

An understanding of normal development can explain the basis for a seemingly diverse set of anomalies (Clinical Correlation 8.1). Ectodermal dysplasias, which are based on abnormalities in the ectodermal germ layer, can include malformations as diverse as thin hair, poorly formed teeth, short stature, dry and scaly skin, and hypoplastic nails (Fig. 8.19). Other syndromes with diverse phenotypic abnormalities are related to defects of the neural crest (see Chapter 12).

Clinical Correlation 8.1 Diagnosis and Treatment of Birth Defects

Only a few decades ago, birth defects were diagnosed only after the fact, and sometimes it was years after birth before certain defects could be discovered and treated. Although this can still happen today, technological changes have permitted earlier diagnosis and treatment of certain congenital malformations.

One of the first advances was the technology associated with karyotyping and sex chromosome analysis. Initially, these techniques were applied after birth to diagnose conditions based on abnormalities in chromosome number or structure. After the development of amniocentesis (the removal of samples of amniotic fluid during early pregnancy), chromosomal analysis could be applied to cells in the amniotic fluid. This approach was particularly useful in the diagnosis of Down syndrome, and it also permitted the prenatal diagnosis of the gender of the infant. Biochemical analysis of amniotic fluid has permitted the diagnosis of numerous inborn errors of metabolism and neural tube defects (the latter through the detection of S-100 protein, which leaks through the open neural tube into the amniotic fluid).

More recently, techniques have been developed for the direct sampling of tissue from the chorionic villi. Molecular genetic analysis of the cells obtained from these samples can now be used to diagnose a wide variety of conditions. The risk-to-benefit ratio of this technique is still being debated.

With the development of imaging techniques such as ultrasound, computed tomography, and magnetic resonance imaging, visualization of fetal morphological structures became possible (see Figs. 18.11 to 18.14). These images can serve as a direct guide to surgeons who are attempting to correct certain malformations by intrauterine surgery. Because surgical wounds in fetuses typically heal without scarring, fetal corrective surgery has distinct advantages (see Chapter 18).