Teratology and Embryological Malformation PDF

TERATOLOGY AND EMBRYOLOGICAL MALFORMATION Gizem SÖYLER, PhD Near East University Faculty of Medicine Department of Histology & Embryology  Teratology is a branch of embryology and pathology that focuses on the development, classification, and causes of malformations in embryos and fetuses. I...

TERATOLOGY AND EMBRYOLOGICAL MALFORMATION Gizem SÖYLER, PhD Near East University Faculty of Medicine Department of Histology & Embryology  Teratology is a branch of embryology and pathology that focuses on the development, classification, and causes of malformations in embryos and fetuses. It is concerned with structural, functional, and metabolic disorders present at birth, which are collectively known as birth defects, congenital malformations, or congenital anomalies. These conditions are studied through teratology and dysmorphology. Teratologic Terms Teratology: The study of birth defects or structural abnormalities that occur during development. Several key terms describe different types of birth defects: Malformation: A structural defect resulting from an intrinsic abnormal developmental process. The defect originates from the abnormal development of the organ or tissue, often due to genetic factors (e.g., chromosomal abnormalities) that disrupt the normal morphogenesis from the earliest stages. Disruption: A structural defect that arises from extrinsic interference with normal development. This could be caused by external factors such as drugs, viruses, or mechanical forces. Unlike malformations, disruptions are not inherited, though genetic predispositions can make one more susceptible.  Deformation: An abnormality in the form, shape, or position of a body part due to mechanical forces, such as oligohydramnios (reduced amniotic fluid), which can compress and distort the fetus. Deformations are often mechanical in origin, as seen in clubfoot caused by uterine compression. Dysplasia: Refers to the abnormal organization of cells within tissues due to issues in histogenesis (tissue formation). Dysplasia affects multiple organs and results from disturbances in cellular development. An example is congenital ectodermal dysplasia. Dysmorphology is the clinical study of these structural abnormalities, focusing on diagnosing and recognizing patterns of defects to better understand their causes and developmental origins.  A key concept in teratology is that certain stages of embryonic development are more vulnerable to environmental disruptions than others. Prior to the 1940s, it was believed that embryos were protected from harmful environmental agents by extraembryonic membranes and maternal tissues. However, in 1941, rubella virus infections were documented to cause birth defects such as cataracts, heart defects, and deafness if contracted during critical periods of eye, heart, and ear development. In the 1950s, thalidomide, a sedative, was found to cause severe limb defects in infants when consumed during early pregnancy. These findings highlighted the role of drugs, viruses, and environmental toxins in causing birth defects, which are estimated to account for 7-10% of cases. Principles of Teratogenesis When evaluating the teratogenic potential of a drug or chemical, three fundamental principles must be taken into account: 1. Critical Periods of Development 2. Dose of the Drug or Chemical 3. Genotype (Genetic Constitution) of the Embryo Periods of Susceptibility to Abnormal Development During pregnancy, embryos experience periods of varying susceptibility to developmental abnormalities. Critical periods of susceptibility occur primarily between weeks 3 and 8 of embryogenesis when major organs and body structures are forming. In the earliest phase, within the first 3 weeks, as exposure either results in embryo death or compensation by the embryo’s early regulatory mechanisms. After the eighth week, structural abnormalities become less common, with later exposure often resulting in functional or growth- related anomalies rather than structural ones.  Each organ has a specific period of heightened vulnerability to teratogens, with earlier-forming organs, like the heart, becoming susceptible sooner than later-forming organs, like the external genitalia. Complex organs, especially the brain and sensory organs, remain sensitive over extended developmental periods. The susceptibility of an embryo to teratogenic agents is significantly influenced by its stage of development at the time of exposure. The most critical periods occur when cell division, differentiation, and morphogenesis are at their peak.  The critical period for brain development spans from 3 to 16 weeks, though disruption may still occur after this period as the brain undergoes rapid differentiation and growth at birth. Environmental disturbances within the first 2 weeks post-fertilization may interfere with zygote cleavage and blastocyst implantation, potentially resulting in early embryonic death or spontaneous abortion. However, these disturbances do not typically lead to birth defects, as teratogens encountered during this period either kill the embryo or are mitigated by the robust regulatory mechanisms of early embryonic development.  Disruption is most pronounced during the organogenetic period (4 to 8 weeks), when teratogens can lead to major birth defects. Physiological defects, like minor morphologic anomalies in external ear structure and functional disturbances such as mental deficiency, may result from disruptions during the fetal period (from the ninth week to birth).  Embryologic timelines are beneficial for understanding potential causes of birth defects; however, it is incorrect to assume that defects arise solely from a single event during the critical period or to pinpoint the exact day of defect manifestation. It can be stated that teratogenic disruption must occur before the end of the critical period for the affected tissue, organ, or part. Birth Defects Birth defects are a leading cause of infant mortality, responsible for 20-25% of infant deaths. They affect about 3% of liveborn infants, though additional defects can be detected later. The causes of birth defects fall into three broad categories: 1. Genetic factors (e.g., chromosomal abnormalities) 2. Environmental factors (e.g., drugs, viruses, and toxins) 3. Multifactorial inheritance (a combination of genetic and environmental factors)  For about 50-60% of birth defects, the cause remains unknown. While minor anomalies, such as microtia (small ears) or pigmented spots, are not harmful themselves, they can be clues to more serious underlying defects.  Major developmental defects, such as spina bifida, are observed in approximately 3% of neonates, and many severe defects occur in early embryos (10-15%), though most of these result in spontaneous abortion during the first six weeks. Chromosomal abnormalities are detected in 50-60% of these aborted embryos. 1a. Birth Defects Caused By Genetic Factors Genetic factors are a leading cause of birth defects, with mutations responsible for about one-third of cases. Errors in mitosis or meiosis can lead to chromosomal abnormalities, which occur in 6-7% of zygotes. Many of these embryos are abnormal and are often spontaneously aborted. Chromosomal changes can be numerical (e.g., trisomy) or structural and may affect either autosomes or sex chromosomes. Individuals with chromosomal abnormalities typically have distinct physical traits related to their condition. Genetic factors cause birth defects by disrupting cellular or tissue development, similar to how teratogens like drugs or infections interfere with normal biological processes. i. Numeric Chromosomal Abnormalities These abnormalities often result from nondisjunction, an error during cell division where a pair of chromosomes or chromatids fail to separate properly during mitosis or meiosis. This causes one daughter cell to receive both chromosomes, while the other gets none. Nondisjunction can occur in either maternal or paternal gametogenesis. Normally, humans have 22 pairs of autosomes; females have two X chromosomes, while males have one X and one Y chromosome. Aneuploidy and Polyploidy Changes in chromosome number can lead to aneuploidy or polyploidy. Aneuploidy refers to any deviation from the normal diploid count of 46 chromosomes and is the most common numeric chromosomal abnormality in humans. An aneuploid individual has a chromosome number that is not a multiple of the haploid number of 23 (e.g., 45 or 47 chromosomes).  The main cause of aneuploidy is nondisjunction during cell division, leading to unequal chromosome distribution between daughter cells. This can result in hypodiploid conditions (e.g., Turner syndrome with 45,X) or hyperdiploid conditions (e.g., trisomy 21, or Down syndrome with 47 chromosomes).  In contrast, a polyploid has a chromosome number that is a multiple of 23 other than diploid (e.g., 69 chromosomes). Polyploid embryos, particularly those with triploidy, are usually nonviable and tend to abort spontaneously in early pregnancy. Polyploidy often results from fertilization of an oocyte by multiple sperm or from failure of a polar body to separate during meiosis. Monosomy and Trisomy Monosomy (missing one chromosome from a pair) and trisomy (an extra chromosome in a pair) are generally caused by nondisjunction during meiosis. Embryos with monosomy (missing a chromosome) typically do not survive, with approximately 99% of embryos lacking a sex chromosome (e.g., 45,X) aborting spontaneously. However, certain sex chromosome abnormalities, such as Turner syndrome (45XO), can result in viable offspring who display a female phenotype but are usually infertile. Monosomy X is the most prevalent cytogenetic abnormality in fetuses that spontaneously abort. In about 75% of cases where nondisjunction leading to monosomy X.  - Turner Syndrome Approximately 1% of monosomy X female embryos survive, leading to a Turner syndrome incidence of about 1 in 8000 live births. Half of those affected have the classic 45,X karyotype, while others exhibit various sex chromosome abnormalities. The phenotype of Turner syndrome is female, but secondary sexual characteristics do not develop in 90% of cases, necessitating hormone replacement therapy.  Trisomy of Autosomes Trisomy refers to the presence of three copies of a specific chromosome in a pair, making it the most common chromosomal abnormality. The primary cause of this numeric error is meiotic nondisjunction, leading to gametes with 24 chromosomes instead of the normal 23, resulting in zygotes with 47 chromosomes. Trisomy is associated with three major syndromes: Trisomy 21 (Down syndrome) Trisomy 18 (Edwards syndrome) Trisomy 13 (Patau syndrome)  Infants with trisomy 13 and 18 are typically severely malformed and mentally deficient, with most dying early in infancy. Over 50% of trisomic embryos abort spontaneously, and the likelihood of trisomy increases with maternal age. Trisomy of Sex Chromosomes Trisomy of the sex chromosomes is a relatively common disorder. Symptoms typically become apparent at puberty. Diagnostic techniques, such as sex chromatin studies, can reveal certain types of trisomy: for instance, XXX females (trisomy X) exhibit two masses of sex chromatin in their nuclei, while XXY males (Klinefelter syndrome) show a similar chromatin mass. The most reliable diagnosis is made through chromosome analysis or other molecular cytogenetic techniques. ii. Structural Chromosomal Abnormalities Structural chromosomal abnormalities primarily arise from chromosome breakage, which can be caused by environmental factors like ionizing radiation, viral infections, drugs, and chemicals. After breakage, the chromosomes may reassemble in abnormal configurations. Such structural abnormalities may sometimes be inherited from a parent, particularly through rearrangements like inversions and translocations. - Translocation Translocation involves transferring a segment of one chromosome to a nonhomologous chromosome. If two nonhomologous chromosomes exchange segments, it's termed reciprocal translocation. This process doesn't always lead to abnormal development; for instance, individuals with a translocation between chromosome 21 and chromosome 14 may appear phenotypically normal but are known as balanced translocation carriers. These individuals have a higher likelihood of producing germ cells with abnormal translocations.  Approximately 3% to 4% of infants with Down syndrome have translocation trisomies, where an extra chromosome 21 is linked to another chromosome. - Deletion In deletion, a chromosome breaks and loses part of its structure. For example, a partial terminal deletion on the short arm of chromosome 5 causes cri du chat syndrome, characterized by a distinctive cat-like cry, microcephaly, severe mental deficiency, and congenital heart defects. A ring chromosome forms when both ends of a chromosome are lost and the ends rejoin to create a ring shape. Though rare, ring chromosomes can occur with any chromosome and have been observed in conditions like Turner syndrome (45,X) and trisomy 18 (Edwards syndrome). Similarly, duplications or inversions of parts of chromosomes occasionally occur during meiosis. These conditions may result in syndromes similar to those seen after the nondisjunction of entire chromosomes. 1b. Birth Defects Caused by Mutant Genes Approximately 7% to 8% of birth defects are attributed to gene defects. A mutation, defined as a permanent, heritable change in the DNA sequence, usually leads to loss or alteration of gene function. Most mutations are detrimental or lethal, and their rate can increase due to environmental factors, such as high doses of ionizing radiation.  Key Genetic Disorders: Achondroplasia: A dominantly inherited condition resulting from a specific mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. Congenital Suprarenal Hyperplasia and Microcephaly: Examples of autosomal recessive defects that manifest only in homozygous individuals, leaving many carriers undetected. Fragile X Syndrome: The second most common inherited cause of moderate intellectual disability. Diagnosis involves chromosome analysis or DNA testing for CGG nucleotide expansions in the FMR1 gene. 2. Birth Defects Caused By Environmental Factors Despite the protective environment of the uterus, human embryos remain vulnerable to various teratogens—agents capable of inducing birth defects or increasing their prevalence within the population. Teratogens can include environmental factors such as infections and drugs, which may mimic genetic conditions when multiple offspring of unaffected parents are affected.  The embryo is particularly susceptible to teratogenic agents during phases of rapid differentiation. Notably, biochemical differentiation occurs prior to morphological differentiation, meaning the sensitivity to teratogens often begins days before observable structural development. Teratogens typically do not induce defects until cellular differentiation has initiated; however, their effects during the first two weeks of development may lead to embryonic death.  The initial cellular response to teratogenic exposure may manifest in various forms (genetic, molecular, biochemical, or biophysical), resulting in diverse cellular changes such as: Cell death Faulty cellular interactions or induction Reduced biosynthesis of substrates Impaired morphogenetic movements Mechanical disruption These pathological changes can ultimately lead to significant outcomes such as intrauterine death, developmental defects, fetal growth retardation, or functional disturbances. Chemical Teratogens Understanding that certain agents can interfere with prenatal development provides a crucial opportunity for preventing some birth defects. When women are informed about the detrimental effects of specific teratogenic agents, such as alcohol, certain environmental chemicals (like polychlorinated biphenyls), and various viruses, they are more likely to avoid exposing their embryos to these harmful substances. Drugs as Teratogens: Certain drugs, like thalidomide, can severely disrupt development, particularly during the organogenetic period (4th to 8th weeks). Others, such as alcohol, cause damage throughout pregnancy. Although drug consumption among pregnant women is high (40% to 90%), only a small percentage of birth defects are caused by drugs and chemicals. Cigarette Smoking: Maternal smoking causes intrauterine growth restriction (IUGR) and can lead to low birth weight, which increases the risk of infant mortality. Nicotine restricts blood flow to the fetus, leading to chronic fetal hypoxia and brain development issues. Alcohol Consumption: Alcohol intake during pregnancy can lead to fetal alcohol syndrome (FAS), which includes growth deficiencies, mental impairment, and physical defects. Even moderate drinking can result in cognitive and behavioral issues. Androgens and Progestogens: Certain progestins and androgens may cause masculinization of female fetuses and increase the risk of cardiovascular defects and other abnormalities. Antibiotics: Drugs like tetracyclines can cause teeth discoloration and bone growth issues in fetuses. High doses of streptomycin may lead to hearing loss in infants. Anticoagulants: Warfarin, a known teratogen, can cause CNS defects, microcephaly, and nasal cartilage hypoplasia. However, heparin is considered safe during pregnancy. Anticonvulsants: Drugs like phenytoin and valproic acid are teratogenic, causing conditions like fetal hydantoin syndrome and neural tube defects. Antineoplastic Agents: Chemotherapy drugs are highly teratogenic, causing severe developmental defects. Methotrexate is particularly harmful, causing skeletal and other birth defects. Corticosteroids: While low doses of corticosteroids are generally safe, NSAIDs should be avoided during late pregnancy to prevent issues like premature closure of the ductus arteriosus. Retinoic Acid: Isotretinoin, used for severe acne, is a potent teratogen, causing craniofacial and neural tube defects. Psychotropic Drugs: Drugs like lithium and benzodiazepines pose risks of heart defects and developmental abnormalities. Environmental chemicals (heavy metals) as teratogens Organic Mercury: Exposure, primarily from consuming fish high in mercury, can lead to fetal Minamata disease. This condition resembles cerebral palsy and causes severe brain damage, mental deficiency, blindness, spasticity, and seizures. Similar effects have been observed in infants whose mothers consumed pork contaminated with mercury.  Lead: Common in both workplaces and the environment, lead crosses the placenta and accumulates in fetal tissues. It is linked to increased miscarriages, fetal defects, intrauterine growth restriction (IUGR), and functional impairments. Children exposed to low lead levels in utero show neurobehavioral and psychomotor disturbances. Polychlorinated Biphenyls (PCBs): These chemicals cause IUGR and skin discoloration. They are often consumed through contaminated sport fish in North America and cooking oil in Japan and Taiwan. Infectious Agents as Teratogens Congenital Rubella: Maternal infection with rubella during the first trimester increases the risk of fetal infection, leading to birth defects such as cataracts, heart defects, deafness, and mental deficiency. Cytomegalovirus (CMV): CMV is the most common viral infection during pregnancy, leading to spontaneous abortion in the first trimester and severe birth defects if contracted later. These defects include IUGR, microcephaly, mental deficiency, blindness, deafness, and liver/spleen enlargement. Asymptomatic infections may cause developmental issues.  Herpes Simplex Virus: This virus increases the risk of miscarriage and premature birth if contracted early in pregnancy. Infected neonates may exhibit cutaneous lesions, microcephaly, microphthalmia, and other birth defects. Varicella-Zoster Virus (Chickenpox): Maternal varicella infection during the first two trimesters can result in skin scarring, limb hypoplasia, eye and brain damage, and mental deficiency. However, infections after 20 weeks carry no proven teratogenic risk.  Human Immunodeficiency Virus (HIV): Fetal HIV transmission primarily occurs during delivery or breastfeeding. In utero infections may result in growth failure, microcephaly, and craniofacial abnormalities. Toxoplasmosis: Caused by the parasite Toxoplasma gondii, usually acquired by eating undercooked meat or contact with infected animals (especially cats). The infection crosses the placenta and can cause brain damage, microcephaly, chorioretinitis, and mental deficiency.  Congenital Syphilis: Treponema pallidum, the bacteria causing syphilis, crosses the placenta early in pregnancy. Without treatment, syphilis can cause stillbirths, congenital deafness, abnormal teeth, bone defects, and mental deficiency. Early treatment of maternal infection can prevent fetal infection and associated defects. Radiation as Teratogen Exposure to high levels of ionizing radiation during pregnancy can harm embryonic cells, causing cell death, chromosome damage, mental deficiency, and physical growth impairments. The effects depend on the dose, rate, and developmental stage of the embryo or fetus at the time of exposure.  Historical cases of pregnant women with cancer receiving large doses of radiation resulted in severe malformations or fetal death. Surviving infants exhibited growth retardation, microcephaly, spina bifida, cataracts, cleft palate, skeletal and visceral defects, and mental deficiency, with the CNS being particularly affected. Studies from Japanese atomic bomb survivors indicate that the brain is most vulnerable between 8 to 16 weeks post-fertilization, with a higher risk of mental deficiency during this time.  Maternal Factors as Teratogens Maternal factors like diabetes and phenylketonuria can act as teratogens during pregnancy, leading to birth defects. Poorly controlled maternal diabetes increases the risk of spontaneous miscarriages and birth defects such as brain anomalies, skeletal defects, and congenital heart issues. Infants of diabetic mothers are often large and face various metabolic complications.  Phenylketonuria, an inborn error of metabolism, increases the risk of microcephaly, cardiac defects, and mental deficiency in offspring if not managed. A phenylalanine-restricted diet can help prevent these complications. Additionally, low levels of folic acid and vitamin B12 in mothers increase the risk of neural tube defects. Mechanical Factors as Teratogen Mechanical factors, such as a reduced quantity of amniotic fluid (oligohydramnios), can act as teratogens by causing deformations in the fetus. These deformations include limb abnormalities like hyperextension of the knee, congenital hip dislocation, and clubfoot. These issues may arise from prolonged fetal compression due to restricted mobility or a malformed uterus.  Additionally, intrauterine amputations or other anomalies can occur due to amniotic bands, which form from ruptured amnion tissue during early pregnancy and constrict fetal growth. 3. Birth Defects Caused By Multifactorial Inheritance Birth defects caused by multifactorial inheritance involve interactions between multiple genes and environmental factors. Common defects, such as cleft lip, cleft palate, neural tube defects (e.g., spina bifida), pyloric stenosis, and congenital dislocation of the hip, can arise from this complex interaction. However, newer research supports a "multiple genes of variable expression" hypothesis, indicating that a few specific genes, interacting in various ways, likely contribute to the development of these conditions. Techniques for Assessing Fetal Growth and Development in Utero 1. Ultrasonography: This noninvasive imaging technique uses high- frequency sound waves to create images of the fetus and surrounding structures, performed either transabdominally or transvaginally. Ultrasound can reveal fetal age, growth, congenital anomalies, amniotic fluid volume, placental position, and multiple gestations. It's crucial for planning pregnancy management, especially in low-birth-weight cases. Measurements of the crown-rump length, biparietal diameter (BPD), femur length, and abdominal circumference are key for assessing fetal development.  2. Amniocentesis: In this procedure, a needle is inserted transabdominally into the amniotic cavity to retrieve 20–30 mL of fluid for biochemical and genetic analysis. Typically performed after 14 weeks of gestation, amniocentesis detects chromosomal abnormalities and genetic markers with high accuracy but requires 1–2 weeks for results. Advances in molecular biology, including PCR, have improved detection of genetic abnormalities.  3. Chorionic Villus Sampling (CVS): CVS involves collecting cells from the placental tissue, offering quicker genetic analysis compared to amniocentesis. Typically performed transabdominally or transvaginally, CVS allows early genetic testing (2–3 days for results). However, it carries a slight risk of limb reduction defects, particularly affecting the digits.  4. Cordocentesis (PUBS): Conducted after the 14th week, cordocentesis involves sampling fetal blood from the umbilical cord to diagnose hematological diseases and chromosomal anomalies. This technique carries a slightly higher risk of fetal loss than amniocentesis and is generally reserved for high-risk cases.  5. Maternal Serum Screening: This screening method assesses maternal blood for biochemical markers, such as AFP, which can indicate fetal abnormalities like neural tube defects, Down syndrome, and other chromosomal conditions. AFP screening, often combined with other markers, is useful in the second trimester but requires confirmatory tests, such as amniocentesis, for positive results.  6. Noninvasive Prenatal Screening (NIPS): NIPS detects fetal DNA circulating in maternal blood as early as 4–6 weeks post-conception. Techniques like FISH and PCR help identify genetic anomalies,including trisomies. NIPS has high predictive accuracy but is used only for screening, with invasive tests required for confirmation.