Genetics and Neoplasm Let us read A.S. Gregor (quoted by Robbins), in writing about Charles Darwin, drawing the inferences of this sort of reasoning in a general way: “ Between the environment and the genes that determine heredity there exists a highly complex relationship. It seems that genes cannot produce normal individuals unless the environmental factors are also normal. What is inherited is a packet of genes transmitted from the parents with the capacity to respond to environmental conditions in certain ways, some of which are called normal for the species in its normal environment.”
Genetic counseling and amniocentesis
Causes of birth defects
Inheritability of congenital disorders
Does the disorder interfere with breeding success? What is the inheritability of acquired characteristics?
A teratogen is any factor that can cause damage to a developing fetus during the prenatal periodod that could cause birth defects. (Schwartz, 1994) The word teratogen comes from the Greek word "teras" meaning "malformation" or "monstrosity". (Berk, 1996)
Prescription, non-prescription, and illegal drugs are all teratogens. In the 1960s a widely used sedative called thalidomide caused defects in many babies. (Schwartz, 1994) About 7,000 infants were affected by it world wide. Defects included deformities of the arms and legs and intelligence was below average. (Berk, 1996)
Aspirin is a teratogen linked to low birth weight, infant death around the time of birth, poorer motor development, and lower intelligence scores. Caffeine is hnked to prematurity, miscarriage, and newborn withdrawal symptoms.
Illegal drugs such as cocaine, heroine, and methadone cause severe problems including prematurity low birth weight, physical defects, breathing difficulties, and death around the time of birth. Also, mfants born to mothers who are addicted to drugs are born addicted to drugs themselves.
Alcohol is a teratogen that causes Fetal Alcohol Syndrome which explains the defects a baby obtains when its mother consumes large amounts of alcohol dunngpregnançy. Mental retardation, poor attention, and overacting are some of the effects.
Hormones can also be teratogens. Diethylbestrol was a hormone widely taken between 1945 and 1970 to prevent miscarriage. It increased the chances of genital tract abnormalities.
Other teratogens include radiation, environmental pollution, and maternal disease. Ion zng radiation can cause mutation which dama&es the DNA in ova and sperm. Effects on the rntant are apparent. The defects include miscarriage, slow physical growth, and underdeveloped brain, and malformations of the skeleton and eyes.
Some examples of environmental pollution include mercury and lead, and polychlornated biphenyls. These teratogens get in food and water supplies, thus reaching the developing fetus. Children become mentally retarded, have abnormal speech, difficulty m chewing and swallowing, and uncoordinated movements.
Usually a mother can get a cold or flu and there will be no real harm to the nthnt but a virus such as rubella has serious effects. Infants affected during the embiyonic period show heart defects, eye cataracts, deafness, genital, urinary, and intestinal abnormalities, and mental retardation. Infants affected during the fetal period show less serious effects, but did show low birth weight, hearing loss, and bone defects.
It is obvious that teratogens cause serious defects in babies, so that is why it is important to warn mothers of their dangers so that they can give birth to healthy babies.
References: Berk, Laura E., Infants, Children, and Adolescents, Allyn and Bacon, Boston, 1996.
Principles of Teratology
mode of action
outcome of exposure
Teratogenesis: Congenital Malformations
agenesis: kidney, dens
aplasia anlage of lung
dysraphic defect spina bifida
involution fail. ductus arteriosis
division failure syndactyly
dysplasia tuberous sclerosis
ectopia hiatus hernia
Time frame for congenital defects
2-5 weeks: CNS, heart
4-7 weeks: Extremities, eyes
6-8 weeks: External genitalia
Thalidomide Thalidomide was never tested on pregnant animals before it was used in humans. After the effects of thalidomide had been established and the drug withdrawn, the same effects were shown to occur in mice, rats, hamsters, rabbits, macaques, marmosets, baboons and rhesus monkeys. As angiogenesis blocker
Disorders of the conceptus
Tend to be all or nothing
Incomplete twinning events
Cleft lip and palate
Mermaid syndrome (syndactyly) Peru's "little mermaid" — the baby born with legs fused from her thighs to her ankles — will undergo delicate surgery Tuesday night to begin repairing her rare birth defect, her doctors said Monday. Milagros Cerron, who celebrated her first birthday April 27, was born with a rare congenital defect known as sirenomelia, or "mermaid syndrome," which occurs in one out of every 70,000 births.
Prenatal surgery for spina bifida, myelomeningocele The tiny hand of a fetus reaches out from a mother's womb to clasp a surgeon's healing finger. It is, by the way, 21 weeks old . . .
Malformations and deformations
Congenital hip dislocation
Club foot or feet
Evolution of the Y chromosome DEGENERATION OF THE Y chromosome occurred in four discrete episodes starting about 300 million years ago, after a reptilelike ancestor of mammals acquired a new gene (SRY) on one of its autosomal chromosomes. Each of the episodes involved a failure of recombination (DNA exchange) between the X and the Y during meiosis, the cell division that yields sperm and eggs. If recombination is blocked, genes in the affected region stop working and decay. The sequence shown is highly simplified. For instance, theY actually expanded temporarily at times (by stitching autosomal DNA into areas still able to recombine), before failures of recombination led to a net shrinkage.
Normal karyotype Nomenclature : n=number of chromosomes xx / xy /x0 explanation as required
“ Superfemales” XXX
“ Supermales” XYY
No-X males Y0
Deletions (Cri du chat), etc.
Chromosomal disorders unrelated to number
Unbalanced translocation and partial additions
Isochromal plane of chromosome separation
Rearranged genes following chromosomal breaks
Down Syndrome Characteristics: Some of the facial features which identify an individual as having Down's syndrome include: Low set ears Up slanting palpebral fissures Low nasal bridge and dorsum Abnormal and excessive facial fat distribution Protruding, enlarged tongue
Patau’s Syndrome The karyotype here demonstrates trisomy 13 (47, XX, +13) also known as Patau's syndrome. It is rare for fetuses with this condition to go to term, so it occurs in only 1 in 6000 live births. It is rare for babies to survive for very long if liveborn because of the multitude of anomalies that are usually present.
Edward’s Syndrome (18)
Partial deletion of the short arm of chromosome 5
Hypertonicity, small and narrow face, dropped jaw, and open-mouth expression secondary to facial laxity.
Often caused by partial deletion chromosome 6
Multifocal (multiple) tumors in retinoblastoma eye
30% cases, 90% penetrance, bilateral tumors
XYY: Supermen? XYY syndrome males inherit an extra Y chromosome--their genotype is XYY. As adults, these "super-males" are usually tall (above 6 feet) and generally appear and act normal. However, they produce high levels of testosterone. During adolescence, they often are slender, have severe facial acne, and are poorly coordinated. They are usually fertile and lead ordinary lives as adults. Many, if not most, are unaware that they have a chromosomal abnormality. The frequency of XYY syndrome is not certain due to statistical differences between different studies. It may be as common as 1 in 900 male births to as rare as 1 in 1500 or even 1 in 2,000. Early studies of XYY syndrome done in European prisons initially led to the erroneous conclusion that these men were genetically predisposed to antisocial, aggressive behavior, below average intelligence, and homosexuality . . . Some researchers suggest that the high testosterone levels of XYY men can make them somewhat more prone to violence and that this may cause higher rates of wife beating.
Types of Dwarfism (not meant to be read!) dwarf (dwarf) an abnormally undersized person. achondroplastic d., a type of dwarf, having a relay tively large head with saddle nose sad brachycephaly, short extremities, and usually lordosis; see also achon.& dropiasio.. Amsterdam ci. a dwarf affected with do Lange*s syndrome. asexuai ci., an adult dwarf with deficient sexual development. ateliotic d., a dwarf whose skeleton is infantile with persistent nonunion between epiphyaes an~ diaphyses bfrd-headed ci., bfrd-headed d. of Seckel, a dwarf with a proportionately small head, a narrow birdlike face with a beaklike protrusion of the nose, large eyes, antimongolaid slant of the palpebral fissures, and receding lower jaw; called also nanocephajic d Briasaud*s ci., one with infantile myxedema. cretin d., a thyroid-deficient dwarf; see cretinism. Called also hypothyroid d. diastrophic d., a dwarf with progressive structural deformities of the bones and joints, including scoliosis, bilateral clubfoot, deformity of the thumb, microineli4, joint contractures and subluxations, malformation of the pinna with calcification of the cartilage, premature calcification of the costal cartilages, and cleft palate. geleophysic ci., a dwarf with a peculiar but pleasant facial appearance and bone dysplasia, especially of the hands and feet. hypophyseal ci., pituitary d. hypothyroid ci., cretin d. infantile ci., a person with marked retardation of mental and physical developm.3nt. Levi-Lorain ci., pituitary d. micromelic ci., a dwarf with very small limbs. nanocephalic ci., bird-headed d. normal ci., a person who is abnormally undersized, but is perfectly formed. Paitauf*s ci., pituitary d. phocomelic ci., a dwarf in whom the diaphyses of the long bones are abnormally short. physiologic ci., normal d. pituitary ci., a dwarf whose retarded development is due tohypofuaction of the anterior pituitary; called also hypophyseai d4 Levi-Lerain d., and Paltauf.g d. primordial ci., pure ci., normal d. rachitic ci., a person dwarfed by rickets, having a high forehead with prominent boeses, bent long bones, and Harrison*s sulcus or groove. renal ci., a dwarf whose failure to achieve normal bone maturation is due to renal failure. Ruaseil ci., see under syndrome sexual ci., a dwarf with normal sexual development. Silver ci., see under syndrome thanatophoric ci., a micromelic dwarf having very short ribs and bones of the extremities, and vertebral bodies that are greatly reduced in height with wide intervertebral spaces; death usually occurs in the first few hours of life, true ci., normal d.b
Mendelian defects (single-gene defects, inborn errors of metabolism)
Phenylketonuria Phenylalanine competes for transport across the blood-brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). Excessive phenylalanine in the blood saturates the transporter, and decreases the levels of other LNAAs in the brain. This leads to disrupted brain development, and thus mental retardation.
Faces of albinism Ocular form
Representative sex-linked disorders
Red-green color blindness
Duchenne muscular dystrophy
Chronic granulomatous disease
Christmas disease (factor IX deficiency, a hemophilia)
Representative codominant disorders
Sickle cell trait vs. disease
Inherited predisposition requires a specific environmental trigger. Examples include:
Birth Defects : some of the abnormalities present at birth such as cleft palate/lip, spina bifida, anencephaly
Cancer : includes bowel, breast, colon, melanoma, ovarian, stomach and others
Cardiovascular : high blood pressure, some causes of heart disease, high cholesterol
Polygenic Inheritance: example of human height One locus for height, with three alleles. Allele h2 adds 2 inches to the average 68-inch height. Allele h0 neither adds nor subtracts from the average height of 68 inches. And allele h- subtracts 2 inches from the average height. Suppose h0 is twice as frequent as either h2 or h-. height # people 64 72
Degree of familial relationship & twin concordance
hereditary neoplasms (retinoblastoma)
viruses & other infectious agents
Lung cancer US distribution
Genetic mutations and cancer
Cancer incidence: Both sexes
Cancer incidence 1989
Cancer incidence by sex 1999
5 year survival rates improving . . .
Colon cancer staging
Malignant vs. Benign tumors
A sarcoma is a cancer of the connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue. This is in contrast to carcinomas, which are of epithelial origin (breast, colon, pancreas, and others)
Sessile vs. pedunculated
To identify a benign tumor, we use the suffix "-oma"; for example, a benign tumor of bone (osseous tissue) would be an osteoma, and a benign tumor of fibrous tissue would be a fibroma (fig.2). Figure 2: Definitions for identifying benign tumors based on the tissue of origin.
The term "adenoma" is used to suggest a benign tumor of a glandular structure or organ, such as a mammary (breast) adenoma or a thyroid adenoma.
The term "papilloma" or "polyp" is applied to wart-like projections from epithelial surfaces like skin or intestine. In some instances, though, the terminology used to name cancers can be misleading.
For example, the commonly-used term "lymphoma" is used to name a malignant tumor of lymphoid tissue; there is no such thing as a benign lymphoid tumor. A better term for this type of cancer might be "lymphosarcoma," which implies malignancy.