Birth Defects PDF

BIRTH DEFECTS Birth defect, congenital malformation, and congenital anomaly are synonymous terms used to describe structural, behavioral, functional, and metabolic disorders present at birth. The science that studies these disorders is teratology. Major structural anomalies occur in 2 to 3% of l...

BIRTH DEFECTS Birth defect, congenital malformation, and congenital anomaly are synonymous terms used to describe structural, behavioral, functional, and metabolic disorders present at birth. The science that studies these disorders is teratology. Major structural anomalies occur in 2 to 3% of live born infants, and an additional 2 to 3% are recognized in children by age 5 years, for a total of 4 to 6%. Birth defects are the leading cause of infant mortality, accounting for approximately 21% of infant deaths. They are the fifth leading cause of years of potential life lost prior to age 65 and a major contributor to disabilities. They are also nondiscriminatory; mortality rates produced by birth defects are the same for Asians, African Americans, Latin Americans, whites, and Native Americans. In 40 to 60% of persons with birth defects, the cause is unknown. Genetic factors, such as chromosome abnormalities and mutant genes, account for approximately 15%; environmental factors produce approximately 10%; a combination of genetic and environmental influences (multifactorial inheritance) produces 20 to 25%; and twinning causes 0.5 to 1%. Minor anomalies occur in approximately 15% of newborns. These structural abnormalities, such as microtia (small ears), pigmented spots, and short palpebral fissures, are not themselves detrimental to health but, in some cases, are associated with major defects. For example, infants with one minor anomaly have a 3% chance of having a major malformation; those with two minor anomalies have a 10% chance; and those with three or more minor anomalies have a 20% chance. Therefore, minor anomalies serve as clues for diagnosing more serious underlying defects. In particular, ear anomalies are easily recognizable indicators of other defects and are observed in virtually all children with syndromic malformations. The causes of birth defects are often divided into:  Genetic factors such as chromosome abnormalities  Environmental factors such as drugs and viruses  Multifactorial inheritance (genetic and environmental factors acting together) BIRTH DEFECTS CAUSED BY GENETIC FACTORS Numerically, genetic factors are the most important causes of birth defects. It has been estimated that they cause approximately one third of all defects. Nearly 85% of all defects have no known causes. Mechanisms as complex as mitosis and meiosis may occasionally malfunction. Chromosomal abnormalities or aberrations are present in 6% to 7% of zygotes (singlecell embryos). Many of these early abnormal embryos never undergo normal cleavage and become blastocysts. 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, and the overall frequency of chromosome abnormalities in these embryos is at least 50%. Two kinds of changes occur in chromosome complements: numerical and structural. The changes may affect the sex chromosomes and/or the autosomes (chromosomes other than sex chromosomes). In some instances, both kinds of chromosomes are affected. Persons with chromosome abnormalities usually have characteristic phenotypes (morphologic characteristics), such as the physical characteristics of infants with Down syndrome. They often look more like other persons with the same chromosome abnormality than their own siblings (brothers or sisters). This characteristic appearance results from 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 a teratogen (e.g. a drug). NUMERICAL CHROMOSOMAL ABNORMALITIES In the United States, approximately one in 120 live-born infants has a chromosomal abnormality. Numerical aberrations of chromosomes usually result from nondisjunction, an error in cell division in which there is failure of a chromosomal pair or two chromatids of a chromosome to disjoin during mitosis or meiosis. As a result, the chromosomal pair or chromatids pass to one daughter cell and the other daughter cell receives neither. Nondisjunction may occur during maternal or paternal gametogenesis. The chromosomes in somatic cells are normally paired; they are 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 chromosome and one Y chromosome. TURNER SYNDROME Approximately 1% of monosomy X female embryos survive; the incidence of 45, X0 (Turner syndrome) in female neonates is approximately 1 in 8000 live births. Half of the affected individuals have 45, X0; the other half has a variety of abnormalities of a sex chromosome. The phenotype of Turner syndrome is female. Secondary sexual characteristics do not develop in 90% of affected females, and hormone replacement is required. Phenotype refers to the morphologic characteristics of an individual as determined by the genotype and the environment in which it is expressed. The monosomy X chromosome abnormality is the most common cytogenetic abnormality observed in fetuses that abort Spontaneously; it accounts for approximately 18% of all abortions caused by chromosome abnormalities. The error in gametogenesis (nondisjunction) that causes monosomy X (Turner syndrome), when it can be traced, is in the paternal gamete (sperm) in approximately 75% of cases; that is, it is the paternal X chromosome that is usually missing. The most frequent chromosome constitution in Turner syndrome is 45, X0; however, nearly 50% of these people have other karyotypes (the chromosome characteristics of an individual cell or a cell line). TRISOMY OF AUTOSOMES The presence of 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 numerical error is meiotic nondisjunction of chromosomes, resulting in a gamete with 24 instead of 23 chromosomes and subsequently in a zygote with 47 chromosomes. Trisomy of the autosomes is associated with three main syndromes. Infants with trisomy 13 and trisomy 18 are severely malformed and mentally deficient; they usually die early in infancy. More than 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 in mothers ages 20 to 24 years, but once in approximately 25 births in mothers 45 years and older. Trisomy 13 is the most common chromosomal abnormality in neonates. Errors in meiosis occur with increasing maternal age and the most common aneuploidy seen in older mothers is trisomy 21. Because of the current trend of increasing maternal age, it has been estimated that by the end of this decade, 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, two or more cell types containing different numbers of chromosomes (normal and abnormal), leads to a less severe phenotype and the IQ of the child may be nearly normal. TRISOMY OF SEX CHROMOSOMES This type of trisomy is a common disorder; however, because there are no characteristic physical findings in infants or children, this disorder is not usually detected until puberty. Sex chromatin studies were useful in the past for detecting some types of trisomy of the sex chromosomes because two masses of sex chromatin are present in nuclei of XXX females (trisomy X), and nuclei of XXY males (Klinefelter syndrome) contain a mass of sex chromatin. Today, diagnosis is best achieved by chromosome analysis or other molecular cytogenetic techniques. STRUCTURAL CHROMOSOMAL ABNORMALITIES Most structural chromosomal abnormalities result from chromosome breakage, followed by reconstitution in an abnormal combination. Chromosome breakage may be induced by various environmental factors, such as ionizing radiation, viral infections, drugs, and chemicals. The type of structural chromosome abnormality depends on what happens to the broken 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 are present in about 1 in 375 neonates. TRANSLOCATION This abnormality 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. Translocation does not necessarily cause abnormal development. Persons with a translocation between a number 21 chromosomes and a number 14 chromosome, for example, are phenotypically normal. Such persons are called balanced translocation carriers; they have a tendency, independent of age, to produce germ cells with an abnormal translocation chromosome. Three to 4% of infants with Down syndrome have translocation trisomies, that is, the extra 21 chromosome is attached to another chromosome. DELETION When a chromosome breaks, part of it may be lost. A partial terminal deletion from the short arm of chromosome 5 causes the cri du chat syndrome. Affected infants have a weak cat-like cry, microcephaly (small neurocranium), severe mental deficiency, and congenital heart disease. A ring chromosome is a type of deletion chromosome from which both ends have been lost, and the broken ends have rejoined to form a ringshaped chromosome. Ring chromosomes are rare but they have been found for all chromosomes. These abnormal chromosomes have been described in persons with 45, X (Turner syndrome), trisomy 18 (Edwards syndrome), and other structural chromosomal abnormalities. BIRTH DEFECTS CAUSED BY MUTANT GENES Seven to 8% of birth defects are caused by gene defects. A mutation, usually involving a loss or change in the function of a gene, is any permanent, heritable change in the sequence of genomic DNA. Because a random change is unlikely to lead to an improvement in development, most mutations are deleterious and some are lethal. The mutation rate can be increased by a number of environmental agents, such as large doses of ionizing radiation. Defects resulting from gene mutations are inherited according to Mendelian laws; consequently, predictions can be made about the probability of their occurrence in the affected person’s children and other relatives. An example of a dominantly inherited birth defect—achondroplasia—results from a G-to- A transition mutation at nucleotide 1138 of the cDNA in the fibroblast growth factor receptor 3 genes on chromosome 4p. Other defects, such as congenital suprarenal hyperplasia and microcephaly, are attributed to autosomal recessive inheritance. Autosomal recessive genes manifest themselves only when homozygous; as a consequence, many carriers of these genes (heterozygous persons) remain undetected. Fragile X syndrome is the most commonly inherited cause of moderate mental deficiency. It is one of more than 200 X-linked disorders associated with mental impairment. The fragile X syndrome has a frequency of 1 in 1500 male births and may account for much of the excess of males in the mentally deficient population. Diagnosis of this syndrome can be confirmed by chromosome analysis demonstrating the fragile X chromosome at Xq27.3, or by DNA studies showing an expansion of CGG nucleotides in a specific region of the FMR-1 gene. Several genetic disorders have been confirmed to be caused by expansion of trinucleotides in specific genes. Other examples include myotonic dystrophy, Huntington chorea, spinobulbar atrophy (Kennedy syndrome), Friedreich ataxia and others. X-linked recessive genes are usually manifest in affected (hemizygous) males, and occasionally in carrier (heterozygous) females, for example, fragile X syndrome. The human genome comprises an estimated 20,000 to 25,000 genes per haploid set or 3 billion base pairs. Because of the Human Genome Project and international research collaboration, many disease- and birth defect–causing mutations in genes have been and will continue to be identified. Most genes will be sequenced and their specific function determined. Understanding the cause of birth defects will require a better understanding of gene expression during early development. The majority of genes that are expressed in a cell are expressed in a wide variety of cells and are involved in basic cellular metabolic functions, such as nucleic acid and protein synthesis, cytoskeleton and organelle biogenesis, and nutrient transport and other cellular mechanisms. These genes are referred to as housekeeping genes. The specialty genes are expressed at specific times in specific cells and define the hundreds of different cell types that make up the human organism. An essential aspect of developmental biology is regulation of gene expression. Regulation is often achieved by transcription factors that bind to regulatory or promoter elements of specific genes. Epigenetic regulation refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. The mechanisms of epigenetic change are not entirely clear, but it is believed that modifying transcriptional factors, DNA methylation, or histone modification may also be key in altering developmental events. Several birth defects may be the result of altered gene expression due to environmental factors, such as stress or altered nutrition rather than due to changes in DNA sequences. Genomic imprinting is an epigenetic process whereby the female and male germ lines confer a sex-specific mark on a chromosome sub region, so that only the paternal or maternal allele of a gene is active in the offspring. In other words, the sex of the transmitting parent will influence expression or non-expression of certain genes in the offspring. This is the reason for PWS and AS, in which case the phenotype is determined by whether the micro deletion is transmitted by the father (PWS) or the mother (AS). In a substantial number of cases of PWS and AS, as well as several other genetic disorders, the condition arises from a phenomenon referred to as uniparental disomy. In the situation with PWS and AS, both chromosomes 15s originate from only one parent. PWS occurs when both chromosomes 15s are derived from the mother, and AS occurs when both are paternally derived. The mechanism for this is believed to begin with a trisomic conceptus, followed by a loss of the extra chromosome in an early post zygotic cell division. This results in a “rescued” cell, in which both chromosomes have been derived from one parent. Uniparental disomy has involved several chromosome pairs. Some are associated with adverse clinical outcomes involving chromosome pairs 6 (transient neonatal diabetes mellitus), 7 (Silver-Russel syndrome), and 15 (PWS and AS), whereas others (1 and 22) are not associated with any abnormal phenotypic effect Homeobox genes are a group of genes found in all vertebrates. They have highly conserved sequences and order. They are involved in early embryonic development and specify identity and spatial arrangements of body segments. Protein products of these genes bind to DNA and form transcriptional factors that regulate gene expression. Disorders associated with some homeobox mutations are described in the table below. DEVELOPMENTAL SIGNALING PATHWAYS Normal embryogenesis is regulated by several complex signaling cascades. Mutations or alterations in any of these signaling pathways can lead to birth defects. Many pathways are cell autonomous and only alter the differentiation of that particular cell, as seen in proteins produced by HOX A and HOX D gene clusters (in which mutations lead to a variety of limb defects). Other transcriptional factors act by influencing the pattern of gene expression of adjacent cells. These shortrange signal controls can act as simple on-off switches (paracrine signals); others, termed morphogens, elicit many responses depending on their level of expression with other cells. One such developmental signaling pathway is initiated by the secreted protein called sonic hedgehog (Shh) that sets off a chain of events in target cells, resulting in activation and repression of target cells by transcription factors in the Gli family. Perturbations (disturbances) in the regulation of the Shh-Patched-Gli (Shh-Ptch- Gli) pathway lead to several human diseases, including some cancers and birth defects. Shh is expressed in the notochord, the floor plate of the neural tube, the brain, and other regions, such as the zone of polarizing activity of the developing limbs, and the gut. Sporadic and inherited mutations in the human Shh gene leads to holoprosencephaly, a midline defect of variable severity involving abnormal central nervous system (CNS) septation, facial clefting, single central incisor, hypotelorism, or a single cyclopic eye. Shh protein needs to be processed to an active form and is modified by the addition of a cholesterol moiety. Defects in cholesterol biosynthesis, such as in the autosomal recessively inherited disorder Smith-Lemli-Opitz syndrome, share many features, particularly brain and limb defects reminiscent of Shh-pathway diseases. This suggests that Shh signaling may play a key role in several genetic disorders. The three Gli genes identified as transcriptional factors are in the Shh-Ptch-Gli pathway. Mutations in the Gli3 gene have been implicated in several autosomal dominantly inherited disorders, including Greig cephalopolysyndactyly syndrome (deletions or point mutations); Pallister-Hall syndrome with hypothalamic hamartomas, central or postaxial polydactyly, among other defects of the face, brain, and limbs (frameshift or nonsense mutations); simple familial postaxial polydactyly type A and B, as well as preaxial polydactyly type IV (nonsense, missense, and frame shift mutations).