Congenital Anomalies Flashcards
Classification of Birth Defects
Time at onset of the injury
Possible etiology
Pathogenesis
Tetraology
Study of abnormal development (causes, mechanisms, & patterns)
More than 20% of infant deaths in North America are due to birth defects!
6-7% Chromosomal Abnormalities 7-8% Mutant Genes 7-10% Environmental Agents 20-25% Multifactorial Inheritance 50-60% Unknown Etiology
Multifactorial Inheritance
Genetic and environmental factors together that cause congenital anomalies.
Two kinds of change that occurs in chromosomes
structural & numerical
What causes numerical chromosomal abnormalities?
Results from non- disjunction.
What is Non-disjunction?
An error in cell division during mitosis or meiosis. This is when there is failure of a chromosomal pair or two chromatids of a chromosome to separate.
What are the 4 clinically significant types of congenital anomalies?
malformation, disruption, deformation, & dysplasia
What is malformation?
Morphologic defect of an organ, part of an organ, or larger region of the body. Due to a defect of a morphogenetic or developmental field and results in complex or multiple malformations.
What is disruption?
A morphologic defect of an organ, part of an organ, or a larger region of the body, due to extrinsic breakdown or interference with an originally normal developmental process. It can not be inherited.
Extra: Teratogens are considered disruptions.
What is deformation?
An abnormal form, shape, or position of a part of the body that results from mechanical forces.
Example: Equinovarus foot resulting from oligohydramnios.
What is dysplasia?
An abnormal organization of cells into tissues and its morphologic results. It is the result of dys-histogenesis (abnormal tissue formation).
Example: Barrett’s Esophagus
What is a syndrome?
A group of anomalies occurring together that have a specific common cause.
This term indicates that a diagnosis has been made and that the risk of recurrence is known.
What is an association?
The non-random appearance of two or more anomalies that occur together more frequently than by chance alone, but the cause is still unknown.
What is the phenotype of children with Turner’s Syndrome?
Monosomy X female embryos, about 1 % of them survive. The phenotype of these children is female.
Extra: In 75% of cases the paternal X chromosome is the one that is missing.
What are the classic features of Turner’s Syndrome?
Short stature, webbed neck, absence of sexual maturation, broad shields like chest with widely spaced nipples, and lymphedema of the hands and feet.
What is the most common cause of abortions caused by chromosomal abnormalities?
Turner’s Syndrome
What is the cause of trisomy?
The cause is usually meiotic nondisjunction of chromosomes, resulting in a gamete with 24 instead of 23 chromosomes, and a zygote with 47 chromosomes.
What is the most common aneuploidy seen in older mothers?
Trisomy 21 aka Down syndrome
Extra: Errors in meiosis occurs with increasing maternal age. Down syndrome occurs once in every 25 births in mothers 45 & older.
Abortion rate for trisomic embryos
More than half spontaneously abort.
What happens to patients 30 years or older with Down Syndrome?
Alzheimer neurofibrillary tangles and plaques.
Characteristics of Trisomy 18 (Edwards Syndrome)
Growth retardation, clenched fists with characteristic positioning of the fingers, (second and fifth ones overlapping the third and fourth), short sternum, and narrow pelvis. These children also present ventricular septal defect, low set malformed ears, hypoplastic nails. They usually die early In infancy.
What is mosaicism?
2 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.
Characteristics of Trisomy 13 or Patau Syndrome
Mental deficiency; severe central nervous system malformations; low set malformed ears, scalp defects, microphtalmia, bilateral cleft lip or palate, polydactyl. A small omphalocele or herniation of viscera into the umbilical cord is present.
When does Trisomy of sex chromosomes usually get detected?
puberty
What is the genotype for Klinefelter Syndrome?
47, XXY
What do 40% of individuals with Klinefelter Syndrome have?
40% of these males have gynecomastia
Characteristics of Klinefelter Syndrome?
small testes hyalinization of seminiferous tubules aspermatogenesis tall with disproportionately long lower limbs varicose veins arterial and venous leg ulcer scant body & pubic hair male hypogonadism sterility with fibrosus of seminiferous tubules marked decrease in testosterone levels elevated gonadotropin levels gynecomastia dull mentality antisocial behavior delayed speech as a child eunuchoid habitus
What causes structural chromosomal abnormalities?
Results from chromosome breakage, followed by reconstitution in an abnormal combination.
What may induce chromosome breakage?
Environmental factors, like drugs, chemicals, and viruses.
structural rearrangement?
The transfer of a piece of one chromosome to a nonhomologous chromosome.
reciprocal translocation
When two nonhomologous chromosomes exchange pieces.
Does translocation always cause abnormal development
Not necessarily, they can be phenotypically normal. They are balanced translocation carriers.
What causes Cri du Chat Syndrome?
A partial terminal deletion from the short arm of chromosome 5.
What are the characteristics of Cri du Chat Syndrome?
Affected infants have a weak catlike cry, microcephaly, severe mental deficiency and congenital heart disease.
How to detect Microdeletions and Microduplications of chromosomes?
High resolution of chromosome bandings
What causes Prader- Willi Syndrome (PWS)?
Deletion of a band in chromosome 15 of paternal origin.
Characteristics of Prader- Willi Syndrome (PWS)?
Short stature, mild mental retardation, obesity, hyperphagia, and hypogonadism (inadequate gonadal function).
What are the characteristics of Angelman Syndrome?
Severe mental retardation, microcephaly, brachycephaly (shortness of head), seizures, and ataxic (jerky) movements of the limbs and
trunk.
What two syndromes are associated with the deletion of band q12 on chromosome 15?
Both Prader- Willi and Angelman syndromes
What is genetic imprinting?
The differential expression of genetic material is dependent on the sex of the transmitting parent.
Example: The clinical phenotype is determined by the parental origin for both Prader- Willi and Angelman syndromes.
fluorescent in situ hybridization (FISH)
Chromosome specific DNA probes can adhere to complementary regions
located on specific chromosomes.
comparative genomic hybridization
Used to detect and map changes in specific regions of the genome.
What is Comparative genomic hybridization used for?
This method is used to identify genomic rearrangements in individuals with mental retardation of unknown cause.
Duplication
A duplicated part of a chromosome, within a chromosome, attached to a chromosome, or as a separate fragment. There is no loss of material, so phenotype may be normal. There may be mental retardation.
Inversion
A chromosomal aberration in which a segment of a chromosome is reversed.
What are the 2 types of inversion?
The inversion can be paracentric, when confined to a single arm of the chromosome; or pericentric when it includes both arms and the centromere.
Isochromosomes
The centromere divides transversely instead of longitudinally. An isochromosome is a chromosome in which one arm is missing and the other is duplicated.
People with isochromosome have what characteristics?
They are short in stature and have other stigmata of Turner syndrome.
Mutant Genes
A mutation involves a loss or change in the function of a gene and is permanent. Some mutations are lethal.
Anomalies Caused by Mutant Genes
Anomalies resulting from gene mutations are inherited according to mendelian laws.
What is the most commonly inherited cause of moderate mental retardation?
Fragile X Syndrome
How to confirm the diagnosis of 200 X linked disorders associated with mental impairment?
Chromosome analysis or DNA studies.
What are housekeeping genes?
genes expressed in almost all cells, involved in basic cellular metabolic functions such as nucleic acid and protein synthesis, cytoskeleton and organelle biogenesis, nutrient transport and other cellular mechanisms.
What do protein products of housekeeping genes do?
Protein products of these genes bind to DNA and form transcriptional factors that regulate gene expression.
Examples of disorders in humans associated with homeobox mutations
Waardenburg Syndrome (type I) Synpolydactyly (type 2) Holoprosencephaly Schizencephaly (type 2)
Characteristics of Waardenburg Syndrome (Type 1)
White forelock, displacement of medial chanti of the eyes, cochlear deafness, facial clefting. Autosomal dominant inheritance.
What gene causes Waardenburg Syndrome (Type 1)?
Mutation of HuP2 gene.
Characteristics of Holoprosencephaly
Incomplete separation of lateral cerebral ventricles, anophthalmia or cyclopia, midline facial hypoplasia or clefts.
What gene causes Holoprosencephaly?
Autosomal dominant inheritance caused by mutation in sonic hedgehog gene.
When is the embryo not susceptible to teratogens?
During the first two weeks.
What is the critical period for brain development?
3 to 16 weeks, but its development can be disrupted after this because the brain is differentiating and growing fast at birth and continues to do so for around 2 more years at last
What happens if a teratogen acts during the first 3 weeks of development?
Death of the embryo
When are malformations of the embryo more frequent?
During weeks 3 to 8
Extra: Later functional disturbance of the fetus may occur.
What does maternal smoking during pregnancy cause?
intrauterine growth restriction (IUGR). In heavy cigarettes smokers (more than 20 per day) premature delivery is twice as frequent, and their infants weigh less than normal.
What does Nicotine cause?
Nicotine constricts uterine blood vessels, causing a decrease in uterine blood flow, lowering the supply of oxygen and nutrients from the maternal blood in the intervillous space of the placenta.
What do high levels of carboxyhemoglobin (due to maternal smoking) alter?
Appears in the maternal and fetal blood and alters the capacity of the blood transport oxygen. As a result, chronic fetal hypoxia may occur and affect fetal growth and development.
Most commonly ingested drugs during pregnancy
Caffeine acetylsalicylic acid (ASA) or aspirin
Both are not teratogens but heavy consumption may cause damage or be harmful to embryo.
Characteristics of Fetal alcohol syndrome
There is microcephaly, short palpebral fissures, epicanthal folds, maxillary hypoplasia, short nose, thin upper lip, abnormal palmar creases, joint anomalies, and congenital heart disease.
What is the most common cause of mental deficiency?
Alcohol Abuse
Extra: Moderate and high levels of alcohol intake during early pregnancy may result in abnormal development. Offspring of chronic alcoholic mothers exhibit prenatal and postnatal growth deficiency, and mental anomalies.
Function of progesterone
Progesterone is a hormone secreted by the corpus luteum to promote and maintain pregnancy.
What does progestin increase?
Progestin increases the prevalence of cardiovascular abnormalities and of hypospadias.
What other properties do progestogens and progestins have?
Some progestogens and progestins have androgenic (masculinizing) properties that may affect the female fetus, producing masculinization of the external genitalia.
What may cause VACTERL syndrome?
Oral contraceptives with progestogens and estrogens, may be teratogenic causing VACTERL.
What does VACTERL stand for?
Vertebral Anal Cardiac Tracheal Esophageal Renal Limbs
What does the human teratogen, Diethylstilbestrol (DES) cause?
Gross and microscopic congenital anomalies of the uterus and vagina in women exposed to it in utero.
What are the 3 types of lesions observed due to DES?
Vaginal adenosis
Cervical erosions
Transverse vaginal ridges
What is adenocarcinoma of the vagina frequent after exposure to?
After DES
What does the antibiotic Tetracycline do?
Produces yellow staining of the deciduous and permanent teeth and also enamel hypoplasia and diminished growth of long bones.
What may cause deafness due to CN VIII damage?
Streptomycin and dihydrostreptomycin, (antituberculosis agents)
Do anticoagulants cross the placenta?
All anticoagulants except heparin cross the placenta membrane and may cause hemorrhage in the embryo or fetus.
What is Warfarin used for?
Warfarin is used in thromboembolic disease and for patients with artificial heart valves.
Why is Warfarin a teratogen?
It causes hypoplasia of the nasal cartilage, and CNS defects. Also causes mental retardation, optic atrophy, and microcephaly..
What are antagonists of vitamin K?
warfarin and coumarin derivatives
What do women with epilepsy need for treatment?
Anticonvulsants which are teratogens!
Examples of teratogenic anticonvulsants
trimethadione
phenytoin
valproic acid
Fetal trimethadione syndrome
Prenatal and postnatal growth retardation, developmental delay, V- shaped eyebrows, low set ears, cleft lip and palate, cardiac, genitourinary, and limb defects.
Phenytoin related birth defects
IUGR, microcephaly, mental retardation, eyelid ptosis, broad depressed nasal bridge, nail or phalangeal hypoplasia, and hernias.
Valproic acid related birth defects
May cause craniofacial, heart, and limb defects. Increases the risk of neural tube defects.
Why are tumor inhibiting chemicals highly teratogenic?
They inhibit mitosis.
What is Methotrexate?
A folic acid antagonist that is used for neoplastic diseases and rheumatoid arthritis. It is a known teratogen that produces major congenital anomalies.
What should corticosteroids be avoided during the last weeks of pregnancy?
Because of the risks of fetal bleeding and premature closure of the ductus arteriosus, nonsteroidal anti-inflammatory drugs should not be taken the last
weeks of pregnancy.
What does cortisone cause in mice?
cleft lip
What are Angiotensin- Converting Enzyme Inhibitors?
They are antihypertensive agents that cause oligohydramnios, fetal death, hypoplasia of the bones of the calvaria, IUGR, and renal dysfunction.
What are 40% of perinatal deaths of diabetic infants the result of?
congenital anomalies
What is the teratogenic level of Tolbutamide?
Tolbutamide has a weak teratogenic level.
What is Tolbutamide used for?
To treat diabetes.
What is Isotretinoin?
It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Isotretinoin is primarily used as a treatment for severe acne. It is a HUMAN TERATOGEN!
Why is Isotretinoin a human teratogen?
It causes craniofacial dysmorphism, cleft palate, thymic aplasia, cardiovascular anomalies, and neural tube defects. Neuropsychological impairment!
What is the best example of an infectious teratogen?
German or three day measles which is a communicable disease.
What is the chance of developmental abnormalities during the first trimester of pregnancy?
20%
Congenital Rubella Syndrome
Cataracts, cardiac defects, and deafness. Mental deficiency, chorioretinitis, glaucoma, microphthalmia, and tooth defects.
Extra: The earlier the infection (Rubella) presents in pregnancy the greater is the danger that the embryo will be malformed.
Rubella infection during 2nd or 3rd Trimester
Infection during the second and third trimesters is low, but functional defects of the CNS, such as mental retardation
and hearing loss may result.
Rubella infection after what gestational month causes no known malformations?
5th month
What starts with a mild fever, tender lymph nodes, later a rash appears on the face and spreads downwards?
Rubella
What type of virus is the rubella virus?
The rubella virus is a togavirus that is enveloped and a single- stranded RNA genome. Highly teratogenic. Crosses the placental membrane.
What is the most common viral infection of the fetus?
Cytomegalovirus (CMV)
Characteristics of CMV in the fetus
Is usually fatal and most pregnancies end in spontaneous abortion.
Extra: Present in 1% of newborns. Newborns affected during the fetal period usually show no clinical signs & are identified through screening programs.
What does CMV infection later in pregnancy results in?
IUGR, microphthalmia, chorioretinitis, blindness, microcephaly, cerebral calcification, mental retardation, deafness, cerebral palsy, and hepatosplenomegaly.
What are cases of asymptomatic CMV infection associated with?
Audiologic, neurologic, and neurobehavioral disturbances in infancy.
What is Toxoplasma gondii?
An intracellular parasite. This parasite may be found in the bloodstream, tissues, or reticuloendothelial cells, leukocytes, and epithelial cells.
How is maternal infection of Toxoplasma gondii usually acquired?
- Eating poorly cooked meat, pork or lamb containing
Toxoplasma cysts - Close contact with infected domestic animals such as cats or infected soil.
When the T. gondii organism crosses the placental membrane and infects the fetus it causes?
Destructive changes in the brain, (intracranial calcifications), and eyes (chorioretinitis) that result in mental deficiency, microcephaly, microphthalmia, and hydrocephaly.
What should pregnant women avoid to prevent toxoplasmosis?
domestic & wild animals
unpasteurized milk
eating of raw or poorly cooked meat
eggs of domestic chickens should be well cooked
True or False:
Mothers of congenitally defective infants are unaware of having had toxoplasmosis.
True
