Birth Defects and Congenital Anomalies

• Congenital anatomic anomalies, birth defects, and congenital malformations are terms to describe developmental disorders present at birth.
• Birth defects are the leading causes of infant mortality and can be structural, functional, metabolic, behavioral, or hereditary.

Classification of Birth Defects

• The International Classification of Diseases (Medicodes' Hospital and Payer, 1995) is the most widely used reference for classifying birth defects.
• The International Classification of Diseases considers time at onset of the injury, possible etiology, and pathogenesis.
• Birth defect, congenital malformation, and congenital anomaly are synonymous terms to describe structural, behavioral, functional, and metabolic disorders present at birth.
• Teratology studies these disorders, derived from "teratos" (monster), also known as Dysmorphology.

Major Determinants of Disease

• Faulty embryo development causes most congenital defects.
• The fetus is vulnerable to injury during weeks 3-8 of embryologic development, when fetal organs form (organogenesis).
• Some congenital diseases arise from inherited genetic defects and might not be apparent at birth.

Teratology: Study of Abnormal Development

• Teratology is the study of the causes, mechanisms, and patterns of abnormal development.
• Stages of embryonic development differ in their vulnerability to disruption.
• Until the 1940s, human embryos were thought to be protected from drugs and viruses by extraembryonic/fetal membranes and the mother's abdominal and uterine walls.
• In 1941, rubella virus was reported to cause severe anatomic anomalies like cataracts, cardiac defects, and deafness if present when the eyes, heart, and ears develop.
• Thalidomide, a sedative, caused severe limb anomalies in infants whose mothers consumed it during early pregnancy.
• This discovery focused attention on the role of drugs in causing human birth defects.

Glossary of Teratologic Terms

• Malformation is a morphologic defect of an organ or body region, that results from an intrinsically abnormal developmental process
• Most malformations are defects from a morphogenetic or developmental field, and respond as a coordinated unit to embryonic interaction, resulting in complex or multiple malformations.
• Malformation is mostly associated with a disorder of tissue development, often in the first trimester.
• Malformation happens when the structures are forming, it may occur as complete, partial absence, or alterations of the structure's normal configuration.
• Disruption refers to morphological alterations of structures after formation due to destructive processes.
• Disruption is a morphologic defect of an organ or body region, that results from extrinsic breakdown of or interference with an originally normal developmental process.
• Alterations that occur after exposure to teratogens are disruptions.
• Disruptions cannot be inherited, but inherited factors can influence the disruption's development.
• Examples of disruption include vascular accidents that lead to bowel atresias and defects made by amniotic bands.
• Deformation results from mechanical forces molding a fetus part over a prolonged period.
• Deformation is an abnormal form, shape, or position of a body part resulting from mechanical forces.
• Deformation is a condition arising from mechanical stress that molds a fetus over a prolonged period to normal tissue; it can occur in the 2nd or 3rd semester due to oligohydramnios.
• Examples of deformation is clubfoot, due to compression in the amniotic cavity and meningomyelocele (severe spina bifida).
• Deformations often affect the musculoskeletal system and might be reversible postnatally.

Congenital Deformations

• Congenital Deformations are those caused by maternal mechanical factors that distort the fetus.
• Usually arise during weeks 35-38 because of maternal factors.
• Maternal factors include a malformed uterus (leiomyomas), multiple fetuses, or decreased amniotic fluid (Oligohydramnios).

Dysplasia

• Dysplasia refers to an abnormal organization of cells into tissue(s) and its morphologic result(s).
• Dysplasia is the process and consequence of dyshistogenesis (abnormal tissue formation).
• Abnormalities relating to histogenesis are classified as dysplasias, e.g., congenital ectodermal dysplasia.
• Dysplasia is causally nonspecific and often affects several organs because of underlying cellular disturbances.
• Descriptive terms are used to describe infants with multiple anomalies with terms, which have evolved to express causation and pathogenesis.
• A polytopic field defect is a pattern of anomalies derived from the disturbance of a single developmental field.
• A sequence is a pattern of multiple anomalies derived from a single known or presumed structural defect or mechanical factor and not a causal concept.
• A syndrome is a pattern of multiple anomalies 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 anomalies and it is not known to be a polytopic field defect, sequence, or syndrome.
• A Syndrome is a group of anomalies occurring together that have a specific common cause (etiology), a determined diagnosis, and a known recurrence risk.
• Association is the nonrandom appearance of two or more anomalies, occurs more frequently than by chance alone, but whose cause is undetermined and whose defects are statistically or causally related.
• Syndrome examples: VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies) and CHARGE (Colobomas, Heart defects, Atresia of the choanae, Retarded growth, Genital anomalies, Ear anomalies).
• Common examples: Syndactyly which is the failure of tissue to divide and polydactyly.

Time of Occurrence of Birth Defects

• The graph represents the timeline of gestation versus the heightened risks of having birth defects.
• The embryonic period, specifically during the third to eighth weeks, is the most sensitive time.
• By the end of eight weeks is when the fetal period begins which will continue until the end of the term.
• During this time, there will be decreased risks of any structural issues happening, but the organ systems could still be affected.
• As the brain continues to make change, it may cause mental retardation or learning disabilities because of the toxic exposures that may happen.

Causes of Human Congenital Anomalies or Birth Defects

• Malformations can occur during structure formation (organogenesis) and could cause complete or partial absence of a structure or changes to a structure's normal configuration.
• Environmental or genetic factors, or a mixture of both, cause malformations.
• Most malformations originate during the third to eighth weeks of gestation.
• The causes of most anomalies are unknown, but 20-25% are caused by a combination of both environmental and genetic factors ( Multifactorial Inheritance).

Minor Anomalies

• Minor anomalies occur in about 15% of newborns.
• Microtia (small ears), pigmentated spots, short palpebral fissures, curvature of the 5th finger (clinodactyly), a third nipple, tiny indentations of the skin near the ears (preauricular pits), and dimples over the lower spine (sacral dimples).
• Minor anomalies are not detrimental to health, but may be 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.
• Minor anomalies are clues for diagnosing serious underlying defects, especially ear anomalies, which are easily recognizable indicators in children with syndromic malformations..

Principles of Teratology

• Factors that determine the capacity of an agent to produce birth defects are known and set forth as the Principles of Teratology.
• Teratogenesis susceptibility depends on the genotype of the conceptus
• The maternal genome is important with respect to drug metabolism, resistance to infection, and other processes that affect the conceptus.
• Susceptibility to teratogens depends on the developmental stage when exposed.
• The most sensitive period for inducing birth defects is during the 3rd-8th week of gestation.
• Each organ system can have one or more susceptibility stages.
• For example, cleft palate can be induced at the blastocyst stage (day 6), during gastrulation (day 14), the early limb bud stage (5th week), or when the palatal shelves are forming (7th week).
• Defects may be induced induced before or after embryogenesis and no stage of development is completely safe.
• Manifestations of abnormal development depend on dose and exposure duration to the teratogen.
• Teratogens have specific ways to act on developing cells and tissues. Mechanisms may involve inhibition of a biochemical or molecular process, pathogenesis (cell death, decreased cell proliferation).
• Manifestations of abnormal development are death, malformation, growth retardation, and functional disorders.
• During the first 2 weeks of development, the embryo is usually not susceptible to teratogens. A teratogen either damages all or most of the cells, resulting in the death of the embryo, or damages only a few cells, allowing the conceptus to recover and the embryo to develop without birth defects.
• Mauve denotes highly sensitive periods when major defects may be produced (e.g., amelia (absence of limbs), neural tube defects, e.g., spina bifida cystica).
• Green indicates stages are stages that are less sensitive to teratogens when minor defects may be induced (hypoplastic thumbs).

Anomalies Caused By Genetic Factors

• Genetic factors are the most important causes of congenital anomalies.
• Genetic factors are estimated to cause about one third of the congenital anatomic anomalies.
• Unknown causes are the source of nearly 85% of anomalies.
• Any mechanism as complex as mitosis or meiosis might occasionally malfunction.
• 6%-7% of zygotes have chromosomal abnormalities or aberrations.
• Chromosomal abnormalities or aberrations are present in single-cell embryos.
• Many abnormal embryos never undergo normal cleavage and usually become blastocysts.
• In vitro studies show high abnormalities in cleaving zygotes less than 5 days old.
• 60% of day 2 cleaving zygotes were found to be abnormal.
• Defective zygotes, blastocysts, and 3-week embryos abort spontaneously
• The overall frequency of chromosome abnormalities in the embryos, this will amount to half of the population.

Numerical Chromosomal Abnormalities

• One in 120 live-born infants in the U.S. has a chromosomal abnormality.
• Numerical aberrations of chromosomes usually result from nondisjunction
• Nondisjunction is an error in cell division in which a chromosomal pair/chromatids of a chromosome fails to disjoin during mitosis or meiosis..
• As a result, the chromosomal pair/chromatids pass to one daughter cell and the other daughter cell receives nothing.
• Nondisjunction may occur during maternal or paternal gametogenesis.
• Chromosomes in somatic cells are normally paired (homologous chromosomes or homologs).
• Normal human females have 22 pairs of autosomes plus two X chromosomes.
• Normal males have 22 pairs of autosomes plus one X chromosome and one Y chromosome.
• Diagram shows nondisjunction of chromosomes during the first meiotic division of a primary oocyte which can then lead to having an abnormal oocyte with 24 chromosomes.
• Subsequent fertilization with a normal sperm can produce a zygote. It will have 47 chromosomes, aneuploidy-deviation starting from the normal diploid number of 46.

Aneuploidy and Polyploidy

• Changes in chromosome number represent either aneuploidy or polyploidy.
• Aneuploidy is any deviation from the 46 chromosome amount.
• Aneuploid is an individual, that has a chromosome which is not an even amount 23 for the haploid (e.g., 45 or 47).
• Polyploidy is an individual that has a chromosome which is an amount 23 for the other person and the haploid (e.g., 69).
• The main cause of Aneuploidy is from cell division.
• One happens during cell division when there’s an unequal amount of homologous in the daughter cells.
• One has two chromosomes and the other has neither chromosome of the pair.
• As a result of what happens the embryo cell starts going either hypodiploid
• hypodiploid (45, has a syndrome)
• hyperdiploid ( usually 47, usually trisomy 22).
• Embryos missing usually die (monosomy).
• 99% of chromosomes cells lack from that sex chromosome, or that cells usually goes and abort spontaneously (45 , X ).

Turner Syndrome (XO)

• 1% of cells that involves chromosome cells is the one that can survive.
• The one that cause to find in someone cell the chromosome is 45.
• The phenotype of turn syndrome comes from the female population.
• If you do or go and make a syndrome will effect the girls.
• Syndrome (nondisjunction) in the sperm around 75% of the time.
• The notes show different features such as :
• Short stature
• Typical face (sphinx)
• Webbed neck
• Renal abnormalities
• Absence of sexual maturation
• Broad shield like chest with widely spaced nipples, and
• Gonadal dysgenesis
• Lymphedema of the hands and feet
• A female fetus that is a 16 weeks with Turner syndrome, most of the time that cell is not in existence.
• 99% of fetuses end up having will abort spontaneously .
• The watery fluid or a hydros starts causing it to look and be excessive amount.
• The hygroma causes it to give that look and give that neck as a loose skin and webbing for the one that seen the same postnatally.

Trisomy of Autosomes

• Three copies of a certain chromosome is called trisomy.
• Trisomies happens when a chromosome is doing a abnormality number.
• The usal amount of this error would be nondisjunction. It helps and takes the results that could cause and goes through the zygote cells that could have 47 different chromes.
• The association of trisomysomes come from three different syndrome :
• Down Syndrome that as trisomy.21
• Trisomy 18 known as the edwards syndrome

Trisomy of Sex Chromosome

• When an chromosome has a disorder. This could effect some of the disorder.
• This disorder doesn’t get detected until puberty. Can cause in the body such as :
• 3xx , sex chromatin usually shows with many problems.
• Today will be best achieved by Chromotins DNA analysis
• Problems and effects with the syndromes of 13 or 8 can cause it come out so differently and to the brain as well because of how mentality it is and could cause dying or dying in early infancy.
• More than half of it may be from some cells or other or early start of what that type of syndrome should look alike.
• Trisomy gets more increase as a number of women age increases.
• For example, when age is at Trisomy and ages as 20 , and 24 birth in that year. But if mothers are age 45 it increases to births with the new cells.
• The common abnormality in the body happens in 25% of children.
• Some of it may involve with syndrome disorders that can cause less severe syndrome defects.