Human Birth Defects

Birth defects (anomalies) are developmental disorders present at birth. Defects are the leading cause of infant mortality (fetal outcome). They may be structural, functional, metabolic, behavioral, or hereditary. Birth defects are a global problem; close to 8 million children worldwide have a serious birth defect.

Classification of Birth Defects

The most widely used reference guide for classifying birth defects is the International Classification of Diseases , but no single classification has universal acceptance. Each classification is limited by being designed for a particular purpose. Numerous attempts to classify human birth defects, especially those that result from errors of morphogenesis (development of form), reveal the frustration and obvious difficulties in the formulation of concrete uniform methodologies for use in medical care. Among clinicians, a practical approach for classifying birth defects that takes into consideration the time of onset of the injury, possible cause, and pathogenesis is now commonly utilized.

Teratology: Study of Abnormal Development

Teratology is the branch of embryology and pathology concerned with the production, developmental anatomy, and classification of malformed embryos and fetuses. A fundamental concept in teratology is that certain stages of embryonic development are more vulnerable to disruption than others ( Fig. 20.1 ). Until the 1940s, it was thought that embryos were protected from environmental agents such as drugs, viruses, and chemicals by their extraembryonic or fetal membranes (amnion and chorion) and their mothers’ uterine and abdominal walls.

Fig. 20.1

Critical periods in human prenatal development. During the first 2 weeks of development, the embryo is usually not susceptible to teratogens; a teratogen damages all or most of the cells, resulting in death of the embryo, or damages only a few cells, allowing the conceptus to recover and the embryo to develop without birth defects. During highly sensitive periods (mauve), major birth defects may be produced (e.g., amelia, absence of limbs, neural tube defects, spina bifida cystica). During stages that are less sensitive to teratogens (green), minor defects may be induced (e.g., hypoplastic thumbs). ASD, Atrial septal defect; CNS, central nervous system; TA, truncus arteriosus; VSD, ventricular septal defect.

In 1941, the first well-documented cases reported that an environmental agent (rubella virus) could produce severe birth defects such as cataracts (see Chapter 18 , Fig. 18.13 ), cardiac defects, and deafness if the rubella infection occurred during the critical period of development of the eyes, heart, and ears. In the 1950s, severe limb defects and other developmental disorders were found in infants of mothers who had used a sedative (thalidomide) during early pregnancy ( Fig. 20.2 ). These discoveries focused worldwide attention on the role of drugs and viruses as causes of human birth defects. An estimated 7% to 10% of birth defects result from the disruptive actions of drugs, viruses, and environmental toxins.

Fig. 20.2

Male neonate has typically malformed limbs (meromelia or limb reduction) resulting from thalidomide ingestion by his mother during the critical period of limb development (see Fig. 20.15 ).

(From Moore KL: The vulnerable embryo. Causes of malformation in man, Manit Med Rev 43:306, 1963.)

More than 10% of infant deaths worldwide (20% in North America) are attributed to birth defects . Major structural defects, such as spina bifida cystica (see Chapter 17 , Fig. 17.15 ), are observed in approximately 3% of neonates. Additional defects can be detected during infancy, and the incidence reaches approximately 6% among 2-year-old children and 8% among 5-year-old children.

The causes of birth defects are divided into three broad categories:

  • Genetic factors such as chromosomal abnormalities

  • Environmental factors such as drugs and viruses

  • Multifactorial inheritance (genetic and environmental factors acting together)

For 50% to 60% of birth defects, the cause is unknown ( Fig. 20.3 ). The defects may be single or involve multiple organ systems and may have major or minor clinical significance. Single minor defects occur in approximately 14% of neonates. Defects of the external ears, for example, are of no serious medical significance, but they may indicate the presence of associated major defects. For instance, the finding of a single umbilical artery alerts the clinician to possible cardiovascular and renal anomalies (see Chapter 7 , Fig. 7.18 ).

Fig. 20.3

The causes of most human birth defects are unknown, and 20% to 25% of them are caused by a combination of genetic and environmental factors (multifactorial inheritance).

Ninety percent of infants with three or more minor defects also have one or more major defects. Of the 3% born with clinically significant defects, multiple major defects are found in 0.7%, and most of these infants die. Major developmental defects are much more common in young embryos (10% to 15%), but most of them abort spontaneously during the first 6 weeks. Chromosomal abnormalities are detected in 50% to 60% of spontaneously aborted embryos.

Birth Defects Caused by Genetic Factors

Numerically, genetic factors are the most important causes of birth defects . Mutant genes cause approximately one third of all defects (see Fig. 20.3 ). Any mechanism as complex as mitosis or meiosis may occasionally malfunction (see Fig. 20.3 ; see Chapter 2 , Figs. 2.1 and 2.2 ). Chromosomal aberrations occur in 6% to 7% of zygotes (single-cell embryos).

Most early abnormal embryos never undergo normal cleavage and become blastocysts (see Chapter 2 , Figs. 2.16 and 2.17 ). In vitro studies of cleaving zygotes less than 5 days old have revealed a high incidence of abnormalities. More than 60% of day 2 cleaving zygotes were found to be abnormal. Many defective zygotes, blastocysts, and 3-week-old embryos abort spontaneously.

Two kinds of changes occur in chromosome complements: numeric and structural. The changes may affect the sex chromosomes or the autosomes (chromosomes other than sex chromosomes). In some instances, both kinds of chromosomes are affected. Persons with chromosomal aberrations usually have characteristic phenotypes (morphologic characteristics), such as the physical characteristics of infants with Down syndrome ( Fig. 20.4 ). They often look more like other persons with the same chromosomal abnormality than their own siblings. This characteristic appearance results from a genetic imbalance . Genetic factors initiate defects by biochemical or other means at the subcellular, cellular, or tissue level. The abnormal mechanisms initiated by the genetic factors may be identical or similar to the causal mechanisms initiated by teratogens , such as drugs and infections ( Table 20.1 ).

Fig. 20.4

A , Anterior view of a female fetus with Down syndrome (trisomy 21) at 16.5 weeks. B , Hand of the fetus shows the single, transverse palmar flexion crease (simian crease, arrow ) and the clinodactyly (incurving) of the fifth digit. C , Anterior view of the faces of dizygotic male twins that are discordant for Down syndrome (trisomy 21). The smaller twin has Down syndrome and developed from a zygote that contained an extra chromosome 21. The characteristic facial features of the syndrome in this infant include upslanting palpebral fissures, epicanthal folds, and a flat nasal bridge. D , A girl, aged 2 years 6 months, who has Down syndrome.

( A and B , Courtesy Dr. D. K. Kalousek, Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. C and D , Courtesy Dr. A. E. Chudley, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, Winnipeg, Manitoba, Canada.)

Table 20.1

Teratogens That Cause Human Birth Defects

Agents Most Common Birth Defects
Alcohol Fetal alcohol syndrome: IUGR, cognitive deficiency, microcephaly, ocular anomalies, joint abnormalities, short palpebral fissures
Androgens and high doses of progestogens Various degrees of masculinization of female fetuses: ambiguous external genitalia resulting in labial fusion and clitoral hypertrophy
Aminopterin IUGR; skeletal defects; CNS malformations, notably meroencephaly (most of the brain is absent)
Carbamazepine NTD, craniofacial defects, developmental retardation
Cocaine IUGR, prematurity, microcephaly, cerebral infarction, urogenital defects, neurobehavioral disturbances
Diethylstilbestrol Abnormalities of uterus and vagina, cervical erosion and ridges
Isotretinoin (13- cis -retinoic acid) Craniofacial abnormalities; NTDs such as spina bifida cystica; cardiovascular defects; cleft palate; thymic aplasia
Lithium carbonate Various defects, usually involving the heart and great vessels
Methotrexate Multiple defects, especially skeletal, involving the face, cranium, limbs, and vertebral column
Misoprostol Limb abnormalities, ocular and cranial nerve defects, autism spectrum disorder
Phenytoin Fetal hydantoin syndrome: IUGR, microcephaly, cognitive deficiency, ridged frontal suture, inner epicanthal folds, eyelid ptosis, broad and depressed nasal bridge, phalangeal hypoplasia
Tetracycline Stained teeth, hypoplasia of enamel
Thalidomide Abnormal development of limbs such as meromelia (partial absence) and amelia (complete absence); facial defects; systemic anomalies such as cardiac, kidney, and ocular defects
Trimethadione Development delay, V -shaped eyebrows, low-set ears, cleft lip and/or palate
Valproic acid Craniofacial anomalies, NTDs, cognitive abnormalities, often hydrocephalus, heart and skeletal defects
Warfarin Nasal hypoplasia, stippled epiphyses, hypoplastic phalanges, eye anomalies, cognitive deficiency
Methylmercury Cerebral atrophy, spasticity, seizures, cognitive deficiency
Polychlorinated biphenyls IUGR, skin discoloration
Cytomegalovirus Microcephaly, chorioretinitis, sensorineural hearing loss, delayed psychomotor/cognitive development, hepatosplenomegaly, hydrocephaly, cerebral palsy, brain (periventricular) calcification
Hepatitis B virus Preterm birth, low birth weight, fetal macrosomia
Herpes simplex virus Skin vesicles and scarring, chorioretinitis, hepatomegaly, thrombocytopenia, petechiae, hemolytic anemia, hydranencephaly
Human parvovirus B19 Fetal anemia, nonimmune hydrops fetalis, fetal death
Rubella virus IUGR, postnatal growth retardation, cardiac and great vessel abnormalities, microcephaly, sensorineural deafness, cataract, microphthalmos, glaucoma, pigmented retinopathy, cognitive deficiency, neonate bleeding, hepatosplenomegaly, osteopathy, tooth defects
Toxoplasma gondii Microcephaly, cognitive deficiency, microphthalmia, hydrocephaly, chorioretinitis, cerebral calcifications, hearing loss, neurologic disturbance
Treponema pallidum Hydrocephalus, congenital deafness, cognitive deficiency, abnormal teeth and bones
Venezuelan equine encephalitis virus Microcephaly, microphthalmia, cerebral agenesis, CNS necrosis, hydrocephalus
Zika virus Microcephaly with partial skull collapse; thin cerebral cortices; retinal mottling and macular scarring; contractures; hypertonia
Varicella virus Cutaneous scars (dermatome distribution), neurologic defects (e.g., limb paresis [incomplete paralysis]), hydrocephaly, seizures, cataracts, microphthalmia, Horner syndrome, optic atrophy, nystagmus, chorioretinitis, microcephaly, cognitive deficiency, skeletal anomalies (e.g., hypoplasia of limbs, fingers, toes), urogenital anomalies
High levels of ionizing radiation Microcephaly, cognitive deficiency, skeletal anomalies, growth retardation, cataracts

CNS , Central nervous system; IUGR , intrauterine growth restriction; NTD , neural tube defect.

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.

Glossary of Teratologic Terms

A birth defect is a structural abnormality of any type, but not all variations of development are defects or anomalies (marked deviation from the average or norm). Anatomical variations are common ; for example, bones vary in their basic shape and in lesser details of surface structure. The four clinically significant types of birth defects are malformation, disruption, deformation, and dysplasia.

  • Malformation is a morphologic defect of an organ, part of an organ, or larger region of the body that results from an intrinsically abnormal developmental process . Intrinsic implies that the developmental potential of the primordium of an organ is abnormal from the beginning, such as a chromosomal abnormality of a gamete (oocyte or sperm) at fertilization. Most malformations are considered to be a defect of a morphogenetic or developmental field that responds as a coordinated unit to embryonic interaction and results in complex or multiple malformations.

  • Disruption is a morphologic defect of an organ, part of an organ, or a larger region of the body that results from the extrinsic breakdown of or an interference with an originally normal developmental process . Morphologic alterations after exposure to teratogens (e.g., drugs, viruses) should be considered as disruptions. A disruption cannot be inherited , but inherited factors can predispose to and influence the development of a disruption.

  • Deformation is an abnormal form, shape, or position of a part of the body that results from mechanical forces . Intrauterine compression in utero that results from oligohydramnios (insufficient amount of amniotic fluid) may produce an equinovarus foot or clubfoot (see Chapter 16 , Fig. 16.15 ). Some central nervous system (CNS) neural tube defects, such as meningomyelocele (severe type of spina bifida), produce intrinsic functional disturbances, which cause fetal deformation (see Chapter 17 , Figs. 17.12 C and 17.15 A ).

  • Dysplasia is an abnormal organization of cells in tissues and its morphologic results. Dysplasia is the process and the consequence of dyshistogenesis (abnormal tissue formation). All abnormalities relating to histogenesis are therefore classified as dysplasias, such as congenital ectodermal dysplasia (see Chapter 19 , box titled “Congenital Ectodermal Dysplasia”). Dysplasia is causally nonspecific and often affects several organs because of the nature of the underlying cellular disturbances.

Other descriptive terms are used to describe infants with multiple defects, and the terms have evolved to express causation and pathogenesis:

  • A polytopic field defect is a pattern of defects derived from the disturbance of a single developmental field.

  • A sequence is a pattern of multiple defects derived from a single known or presumed structural defect or mechanical factor.

  • A syndrome is a pattern of multiple defects thought to be pathogenetically related and not known to represent a single sequence or a polytopic field defect.

  • An association is a nonrandom occurrence in two or more individuals of multiple defects not known to be a polytopic field defect, sequence, or syndrome.

Whereas a sequence is a pathogenetic (causing disease or abnormality) and not a causal concept, a syndrome often implies a single cause, such as trisomy 21 (Down syndrome). In both cases, the pattern of defects is known or considered to be pathogenetically related. In the case of a sequence, the primary initiating factor and cascade of secondary developmental complications are known. For example, Potter syndrome ( sequence ), which is attributed to oligohydramnios (insufficient amount of amniotic fluid), results from renal agenesis or leakage of amniotic fluid (see Chapter 12 , Fig. 12.12 C ). An association, in contrast, refers to statistically, not pathogenetically or causally, related defects. One or more sequences, syndromes, or field defects may constitute an association.

Dysmorphology is an area of clinical genetics that is concerned with the diagnosis and interpretation of patterns of structural defects. Recurrent patterns of birth defects enable syndrome recognition . Identifying these patterns in individuals has improved understanding of the causes and pathogenesis of these conditions.

Phenotype refers to the morphologic characteristics of a person as determined by the genotype and environment in which it is expressed.

Inactivation of Genes

During embryogenesis, one of the two X chromosomes in female somatic cells is randomly inactivated and appears as a mass of sex chromatin . Inactivation of genes on one X chromosome in somatic cells of female embryos occurs during implantation. X inactivation is important clinically because it means that each cell from a carrier of an X-linked disease has the mutant gene causing the disease on the active X chromosome or on the inactivated X chromosome that is represented by sex chromatin. Uneven X inactivation in monozygotic (identical) twins is one reason given for discordance in a variety of birth defects. The genetic basis for discordance is that one twin preferentially expresses the paternal X and the other the maternal X.

Aneuploidy and Polyploidy

Changes in chromosome number result in aneuploidy or polyploidy. Aneuploidy is any deviation from the diploid number of 46 chromosomes. In humans, this disorder is the most common and clinically significant of numeric chromosomal abnormalities . It occurs in 3% to 4% of clinically recognized pregnancies. An aneuploid is an individual who has a chromosome number that is not an exact multiple of the haploid number of 23 (e.g., 45, 47). A polyploid is a person who has a chromosome number that is a multiple of the haploid number of 23 other than the diploid number (e.g., 69; Fig. 20.6 ).

The principal cause of aneuploidy is nondisjunction during cell division (see Fig. 20.5 ), which results in an unequal distribution of one pair of homologous chromosomes to the daughter cells. One cell has two chromosomes, and the other has neither chromosome of the pair. As a result, the embryo’s cells may be hypodiploid (45,X, as in Turner syndrome; Figs. 20.7 to 20.9 ) or hyperdiploid (usually 47, as in trisomy 21 [Down syndrome]; see Fig. 20.4 ).

Fig. 20.5

Nondisjunction of chromosomes during the first meiotic division of a primary oocyte results in an abnormal oocyte with 24 chromosomes. Subsequent fertilization by a normal sperm produces a zygote with 47 chromosomes (aneuploidy), which is a deviation from the human diploid number of 46.

Fig. 20.6

Triploid fetus (69 chromosomes) illustrates severe head-to-body disproportion. Triploid fetuses account for almost 20% of chromosomally abnormal miscarriages.

(From Crane JP: Ultrasound evaluation of fetal chromosome disorders. In Callen PW, editor: Ultrasonography in obstetrics and gynecology, ed 3, Philadelphia, 1994, Saunders.)

Fig. 20.7

Female infant with Turner syndrome (45,X). A , Face of the infant. B , Lateral view of the infant’s head and neck shows a short, webbed neck and prominent ears. Infants with this syndrome have defective gonadal development (gonadal dysgenesis). C , The infant’s feet show the characteristic lymphedema (puffiness and swelling), which is a useful diagnostic sign. D , Lymphedema of the toes is a condition that usually leads to nail underdevelopment (hypoplasia).

(Courtesy Dr. A. E. Chudley, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, Winnipeg, Manitoba, Canada.)

Fig. 20.8

Turner syndrome (45,X) in a 14-year-old girl. Features of the syndrome include short stature; a webbed neck; absence of sexual maturation; a broad chest with widely spaced nipples; and lymphedema swelling of the hands and feet.

(Courtesy Dr. F. Antoniazzi and Dr. V. Fanos, Department of Pediatrics, University of Verona, Verona, Italy.)

Fig. 20.9

Female fetus with Turner syndrome (45,X) at 16 weeks. Notice the excessive accumulation of watery fluid (hydrops) and the large cystic hygroma (lymphangioma) in the posterior head and cervical region. The hygroma causes the loose neck skin and webbing seen postnatally (see Fig. 20.3 B ).

(Courtesy Dr. A. E. Chudley, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, Winnipeg, Manitoba, Canada.)

Turner Syndrome

Approximately 1% of monosomy X female embryos survives; the incidence of 45,X (Turner syndrome) in female neonates is approximately 1 in 8000 live births. The most frequent chromosome constitution in Turner syndrome is 45,X; however, almost 50% of these people have other karyotypes (chromosomal characteristics of an individual cell or cell line). The phenotype of Turner syndrome is female (see Figs. 20.7 to 20.9 ). Secondary sexual characteristics do not develop in 90% of affected females, and hormone replacement is required.

The monosomy X chromosome abnormality is the most common cytogenetic abnormality observed in fetuses that abort spontaneously (see Fig. 20.9 ); it accounts for approximately 18% of all abortions caused by chromosomal abnormalities. The error in gametogenesis (nondisjunction) that causes monosomy X, when it can be traced, is in the paternal gamete (sperm) in approximately 75% of cases it is (i.e. the paternal X chromosome that is usually missing).

Trisomy of Autosomes

Three chromosome copies in a given chromosome pair is called trisomy . Trisomies are the most common abnormalities of chromosome number. The usual cause of this numeric error is meiotic nondisjunction of chromosomes (see Fig. 20.5 ), which results in a gamete with 24 instead of 23 chromosomes and subsequently in a zygote with 47 chromosomes. Trisomy of autosomes is mainly associated with three syndromes ( Table 20.2 ):

  • Trisomy 21 or Down syndrome (see Fig. 20.4 )

  • Trisomy 18 or Edwards syndrome ( Fig. 20.10 )

    Fig. 20.10

    A female neonate with the trisomy 18 syndrome has growth retardation, clenched fists with characteristic positioning of the fingers (second and fifth ones overlapping the third and fourth ones), short sternum, and narrow pelvis.

    (Courtesy Dr. A. E. Chudley, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, Winnipeg, Manitoba, Canada.)

  • Trisomy 13 or Patau syndrome ( Fig. 20.11 )

    Fig. 20.11

    A female neonate with trisomy 13 syndrome has a bilateral cleft lip, low-set and malformed left ear, and polydactyly (extra digits). A small omphalocele (herniation of viscera into umbilical cord) can be seen.

    (Courtesy Dr. A. E. Chudley, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, Winnipeg, Manitoba, Canada.)

Table 20.2

Trisomy of Autosomes

Chromosomal Aberration and Syndrome Incidence Usual Clinical Manifestations
Trisomy 21 (Down syndrome) * (see Fig. 20.6 ) 1 in 800 Cognitive deficiency; brachycephaly, flat nasal bridge; upward slant to palpebral fissures; protruding tongue; transverse palmar flexion crease; clinodactyly of the fifth digit; congenital heart defects; gastrointestinal tract abnormalities
Trisomy 18 syndrome (Edwards syndrome) (see Fig. 20.7 ) 1 in 8000 Cognitive deficiency; growth retardation; prominent occiput; short sternum; ventricular septal defect; micrognathia; low-set, malformed ears, flexed digits, hypoplastic nails; rocker-bottom feet
Trisomy 13 syndrome (Patau syndrome) (see Fig. 20.8 ) 1 in 12,000 Cognitive deficiency; severe central nervous system malformations; sloping forehead; malformed ears, scalp defects; microphthalmia; bilateral cleft lip and/or palate; polydactyly; posterior prominence of the heels

* The incidence of trisomy 21 at fertilization is greater than at birth; however, 75% of embryos are spontaneously aborted, and at least 20% are stillborn.

Infants with this syndrome rarely survive beyond 6 months.

Infants with trisomy 13 and trisomy 18 are severely malformed and have major neurodevelopmental disabilities. These life-limiting disorders have a 1-year survival rate of approximately 6% to 12%. More than one half of trisomic embryos spontaneously abort early. Trisomy of the autosomes occurs with increasing frequency as maternal age increases. For example, trisomy 21 occurs once in approximately 1400 births among mothers between the ages of 20 and 24 years but once in approximately 25 births among mothers 45 years and older ( Table 20.3 ). The most common aneuploidy seen in older mothers is trisomy 21 (Down syndrome ; see Fig. 20.4 ).

Table 20.3

Incidence of Down Syndrome Among Neonates

Maternal Age (Years) Incidence
20–24 1 in 1400
25–29 1 in 1100
30–34 1 in 700
35 1 in 350
37 1 in 225
39 1 in 140
41 1 in 85
43 1 in 50
45+ 1 in 30

The Centers for Disease Control and Prevention notes that the incidence of trisomy 21 syndrome in the United States is estimated to be between 1 in 1000 and 1 in 1100 live births. Because of the current trend of increasing maternal age, it has been estimated that children born to women older than 34 years will account for 39% of infants with trisomy 21. Translocation or mosaicism occurs in approximately 5% of the affected children. Mosaicism , which is a condition in which two or more cell types contain different numbers of chromosomes (normal and abnormal), leads to a less severe phenotype, and any cognitive effects may be minor.

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.


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.


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.


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) .

Fig. 20.12

A male adolescent with Klinefelter syndrome (XXY trisomy) has breasts. Approximately 40% of males with this syndrome have gynecomastia (development of breasts) and small testes.

(Courtesy Children’s Hospital, Winnipeg, Manitoba, Canada.)

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.


Translocation is the transfer of a piece of one chromosome to a nonhomologous chromosome. If two nonhomologous chromosomes exchange pieces, it is called a reciprocal translocation (see Fig. 20.13 A and G ). Translocation does not necessarily cause abnormal development. For example, persons with a translocation (Robertsonian) between a number 21 chromosome and a number 14 chromosome (see Fig. 20.13 G ) are phenotypically normal. They are called balanced translocation carriers . They have a tendency, independent of age, to produce germ cells with an abnormal translocation chromosome . Between 3% and 4% of infants with Down syndrome have translocation trisomies ; the extra chromosome 21 is attached to another chromosome. Translocations are the most common structural abnormality of chromosomes in the general population (1 : 1000).


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.

Fig. 20.14

A , Male child with cri du chat (“cat-like cry”) syndrome has microcephaly and hypertelorism (increased distance between orbits). B , Partial karyotype of the child shows a terminal deletion of the short arm (end) of chromosome 5. The arrow indicates the site of the deletion.

( A , From Gardner EJ: Principles of genetics , ed 5, New York, 1975, John Wiley & Sons. B , Courtesy the late Dr. M. Ray, Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.)

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.


Inversion is a chromosomal aberration in which a segment of a chromosome is reversed. Paracentric inversion is confined to a single arm of the chromosome (see Fig. 20.13 E ), whereas pericentric inversion involves both arms and includes the centromere. Carriers of pericentric inversions risk having offspring with birth defects because of unequal crossing over and malsegregation at meiosis (see Chapter 2 , Fig. 2.2 ).


Some abnormalities are represented as a duplicated part of a chromosome within a chromosome (see Fig. 20.13 D ), attached to a chromosome, or as a separate fragment. Duplications are more common than deletions and are less harmful because there is no loss of genetic material . However, the resulting phenotype often includes cognitive impairment or birth defects. Duplication may involve part of a gene, a whole gene, or a series of genes.

Microdeletion and Microduplication

With high-resolution banding techniques , very small interstitial and terminal deletions in several chromosomal disorders have been detected. An acceptable resolution of chromosome banding on routine analysis reveals 550 bands per haploid set, whereas high-resolution chromosome banding reveals up to 1300 bands per haploid set. Because the deletions span several contiguous genes, these disorders and those with microduplications are referred to as contiguous gene syndromes ( Table 20.5 ), as in these examples:

  • Prader–Willi syndrome (PWS) is a sporadically occurring disorder associated with short stature, mild cognitive deficiency, obesity, hyperphagia (overeating), and hypogonadism.

  • Angelman syndrome (AS) is characterized by severe cognitive deficiency, microcephaly , brachycephaly , seizures, and ataxic (jerky) movements of the limbs and trunk.

PWS and AS are often associated with a visible deletion of band q12 on chromosome 15. The clinical phenotype is determined by the parental origin of the deleted chromosome 15. If the deletion is in the mother, AS occurs; if passed on by the father, the child exhibits the PWS phenotype. This suggests the phenomenon of genetic imprinting , in which differential expression of genetic material depends on the sex of the transmitting parent. One of the two parental alleles is active and the other inactive because of epigenetic factors. Loss of expression of the active allele leads to neurodevelopmental disorders.

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