Genetics - Endocrine / Reproductive Block (I) Flashcards
What are the three categories of genetic disorder?
- Chromosomal
- Metabolic
- Syndromic
Define: mosaicism.
An individual with two genetically distinct cell lines coming from a single zygote
True/False.
Mosaicism results from a meiotic non-disjunction event occuring in the pre-zygotic phase.
False.
Mosaicism results from a mitotic non-disjunction event occuring in the post-zygotic phase.
Define: nondisjunction.
The failure of chromosomes to separate during meiosis I or mitosis (or sister chromatids during meiosis II)
What is here described?
The failure of two homologous chromosomes to separate during meiosis I, or two chromatids of a chromosome to separate in meiosis II or mitosis resulting in one daughter cell with two homologous chromosomes and the other with none.
Nondisjunction
What are three infant S/Sy that indicate you might need to check for chromosomal abnormalities?
- Growth restriction
- Structural abnormalities (especially >1)
- Developmental delay, or mental retardation
What type of genetic disorder is characterized by some mixture of the following?
- Growth restriction
- Structural abnormalities, especially more than one
- Developmental delay, or mental retardation
Chromosomal abnormalities
What are two common causes of trisomies?
- Nondisjunction (often due to advanced maternal age)
- Translocation
What is the most common form of chromosomal translocation?
14;21 Robertsonian translocation
What risk of Down syndrome does a woman’s pregnancy carry if the woman is 20?
35?
40?
49?
- 06%
- 3%
- 0%
- 1%
If a woman has given birth to a child with Down syndrome, is there a difference to future pregnancies whether the Down syndrome was caused by trisomy 21 or 14;21 Robertsonian translocation?
Yes.
If trisomy 21:
there is a 1% risk until about age 40 (then normal age risks)
If 14;21 Robertsonian translocation:
– de novo: not significantly higher
– maternal carrier: 10-15%
– paternal carrier: 3- 5%
What percentage of Down syndrome cases are due to trisomy 21?
What percentage are due to translocations?
What percentage are due to trisomy mosaicism?
95%
4%
1%
What is the genetic cause of the vast majority of cases of Down syndrome?
Trisomy 21 (95%)
What are the classical S/Sy of Down syndrome?
Mental retardation,
hypotonia, protruding tongue, short stature,
upslanting palpebral fissures, epicanthal folds,
transverse palmar crease, clinodactaly of 5th finger
What intestinal and ocular signs are often present in Down syndrome?
Intestinal: duodenal atresia
Ocular: speckled iris (Brushfield spots)
What cardiac complications often exist in patients with Down syndrome?
Atrio-ventricular canal;
VSD
True/False.
Individuals with Down syndrome are at a higher risk for Alzheimer’s disease, leukemia, hypothyroidism, and cataracts.
True.
What is the genetic cause of Edward’s syndrome?
Trisomy 18
What is the genetic cause of Patau syndrome?
Trisomy 13
How long do patients with Edward’s syndrome typically live?
< 1 year
List a few of the common S/Sy of Edward’s syndrome.
How long do these patients typically live?
Microcephaly, prominent occiput, low set ears,
clenched hands (index finger overlies 3rd finger)
< 1 year
What non-neurological organ system is often severely affected in patients with Edward’s syndrome?
>90% have congenital heart disease
How common is Down syndrome?
How common is Edward’s syndrome?
How common is Patau syndrome?
1/1000
1/10,000
1/15,000
What is the life expectancy for an individual with Down syndrome?
What is a common cause of death?
60s
congenital heart disease
What is the life expectancy for an individual with Patau syndrome?
~85% are < 1 year;
rarely, some may reach adulthood
Describe some of the visible clinical features of Patau syndrome.
Cleft lip/palate (midline usually): 70%;
abnormal ears, scalp defects;
polydactyly;
omphalocele
Describe some of the non-visible clinical features of Patau syndrome.
Holoprosencephaly, mental retardation;
congenital heart abnormalities;
single umbilical artery
What are some of the heart abnormalities associated with Patau syndrome?
VSD
PDA
ASD
Which autosomal monosomies are survivable?
None
(unless mosaic with a normal cell line)
What is it called if an individual receives an extra 23 chromosomes from one of their parents?
Triploidy
True/False.
Triploidy in humans is an example of genetic imprinting, depending on whether the error was received from the father or the mother.
True.
What is the genetic cause and effect if an individual receives an extra 23 maternal chromosomes (triploidy)?
- Digyny (triploid zygote –> haploid sperm and diploid egg)
- Small placenta, very growth-restricted fetus
What is the genetic cause and effect if an individual receives an extra 23 paternal chromosomes (triploidy)?
- Dispermy, paternal nondisjunction
- Large hydropic placenta (incomplete mole);
3,4 syndactyly, macrocephaly, deformed face, other malformations
Which is more useful in chromosomal analysis, prometaphase or metaphase analysis?
Why?
Prometaphase;
improved band resolution + detection of smaller deletions
A newborn presents with a small face, large nose, and large mouth. The patient shows poor motor tone and is making a high-pitched ‘mewling’ like that of a cat.
What is the diagnosis? What is the cause?
Cri-du-Chat syndrome;
microdeletion on chromosome 5p
Describe Cri-du-Chat syndrome.
Affected chromosome: 5p
characteristic newborn cry like a cat;
small face, large nose, large mouth;
failure to thrive, developmental delay, hypotonia
Describe the presence of fetal testis on development of the Wolffian or Mullerian ducts.
Leydig cells –> testosterone –> mesonephric (Wolffian) differentiation
Sertoli cells –> MIF –> paramesonephric (Mullerian) degeneration
What structures are formed due to the effects of fetal testosterone?
What structures are formed due to the effects of fetal dihydrotestosterone?
Epididymus, vas deferens, seminal vesicles;
penis, prostate, scrotum
Describe the effects of fetal ovaries on development of the Wolffian or Mullerian ducts.
Mesonephric (Wolffian) degenerate (due to the lack of testosterone);
paramesonephric (Mullerian) develop (due to the lack of MIF)
What adult structures develop from the paramesonephric (Mullerian) ducts?
The upper 1/3 of the vagina,
the uterus,
the Fallopian tubes
Define: Lyonization.
At ~2 weeks post-fertilization, one X chromosome in each cell of the female embryo becomes inactive
What process is defined below?
At ~2 weeks post-fertilization, one X chromosome in each cell of the female embryo becomes inactive
Lyonization
Define: gonadal dysgenesis.
Poorly developed or streak gonads due to various causes
What term describes the following:
an individual born with both ovarian and testicular tissue.
True hermaphroditism
List the genetic makeup of each of the following cases:
Kleinfelter’s syndrome
Turner’s syndrome
Trisomy X
Androgen insensitivity
47, XXY
45, XO
47, XXX
46, XY
What is male pseudohermaphroditism?
An XY male with externally ambiguous or feminine genitalia
What is female pseudohermaphroditism?
An XX female with externally ambiguous or masculine genitalia
Classic Turner’s syndrome involves complete loss of what?
An X chromosome
(45,X0)
Turner’s syndrome can also result from a loss of the X p arm or q arm. Describe the differences.
46, XX, Xp-: short stature; congenital malformations
46, XX, Xq-: gonadal dysfunction
What medication(s) can be given to treat Turner’s syndrome?
Estrogen, progesterone, growth hormone
True/False.
Turner’s syndrome leads to the following S/Sy:
cystic hygromas, short stature, cardiac and renal abnormalities, mental retardation, lack of development of secondary sexual characteristics.
False.
Turner’s syndrome leads to the following S/Sy:
cystic hygromas, short stature, cardiac and renal abnormalities, average intelligence (no mental retardation), lack of development of secondary sexual characteristics.
What is the mechanism of Kleinfelter’s syndrome?
Meiotic nondisjunction
Describe the development, puberty, and fertility of an individual with Kleinfelter’s syndrome.
Development: Normal (tall, thin); IQ slightly less than normal; behavioral problems
Puberty: Small testis; hypogonadism, gynecomastia
Reproduction: Infertile (hylanized tubules; azoospermia)
How is Kleinfelter syndrome treated?
Testosterone replacement
Describe the development and fertility of a 47, XYY male.
Development: Normal male; tall; behavioral problems
Fertility: normal
What is the cause of 47,XYY defects?
Paternal nondisjunction
Describe the development and fertility of a 47,XXX individual.
Development: Normal female; development: tall; low IQ
Reproduction: Many infertile
What is the cause of androgen insensitivity syndrome?
No androgen receptor in target cells
How do individuals with androgen insensitivity syndrome present at birth?
What is their karyotype?
As females;
46,XY
Describe the developmental effects of androgen insensitivity syndrome.
Development: Feminization; incomplete adrenarche; amenorrhea; small clitoris/labia;
lower 2/3 of the vagina; absent uterus and tubes and mesonephric structures
What is the risk of gonadal neoplasia in an individual with androgen insensitivity syndrome?
2 - 5%
What is the risk of poorly differentiated gonadal tissue in an intraabdominal environment?
Increased risk of gonadal carcinoma
What should occur if a 46,XY individual has any form of gonadal dysgenesis?
Surgical removal of gonadal tissue
What do 46,XY/45,X0 and 46,XX/45,X0 karyotypes describe?
Male and female forms of mosaic Turner’s syndrome
What karyotype is known as a ‘super male’?
What karyotype is known as a ‘super female’?
XYY
XXX
What gene determines sexual differentiation?
SRY
What is Fragile X syndrome?
What is the genetic defect?
Which parent is more likely to pass on / worsen this defect?
X-linked mental retardation;
CGG repeats in the FMR1 gene;
maternal
What are two disorders displaying anticipation?
Fragile X syndrome;
Huntington’s disease
In working up potential Fragile X syndrome, how can genetic testing be performed?
a) Southern analysis — separates trinucleotide repeat segments based on size
b) PCR — will give size of mutation (best for premutations)
Best to do both
Define: infertility.
(1) Inability to achieve conception or (2) inability to sustain a pregnancy through to live birth
What are a few chromosomal abnormalities associated with infertility?
- Turner’ syndrome
- Kleinfelter’s syndrome
- X chromosome abnormalities
- Y chromosome microdeletions
- Translocations (reciprocal and Robertsonian)
True/False.
Some genes are expressed preferentially in either the parental or maternal genotype.
True.
How is genetic imprinting regulated?
Epigenetics (extrinsic to changes in primary nucleotide sequence)
- DNA methylation
- Histone modification
- Non-coding RNAs
Define: genetic imprinting.
The differential modification of the maternal and paternal genetic contribution to the zygote
Define: uniparental disomy.
The inheritance of a pair of chromosomes from one parent with no copy of that chromosome from the other parent.
Give the term described below.
The inheritance of a pair of chromosomes from one parent with no copy of that chromosome from the other parent.
Uniparental disomy
Describe the subtype of uniparental disomy below:
Isodisomy
Two copies of the same homolog from one parent
Describe the subtype of uniparental disomy below:
Heterodisomy
One copy of each homolog from the same parent
Describe the subtype of uniparental disomy below:
Segmental UPD
A segment of a chromosome is present from the same parent
Describe trisomy rescue as a cause of uniparental disomy.
True/False.
All of the following are potential causes of uniparental disomy:
- Trisomy Rescue
- Monosomy Rescue
- Gametic Complementation
- Somatic Crossing-over
- Robertsonian Translocation
True.
70% of cases of Prader-Willi syndrome are caused by a deletion of:
25% of cases of Prader-Willi syndrome are caused by:
5% of cases of Prader-Willi syndrome are caused by:
Paternal chromosome 15 genetic material
maternal uniparental disomy of chromosome 15
imprinting center defects
What is the basic etiology of Prader-Willi syndrome?
Loss of function of a group of genes normally expressed on the paternal chromosome 15
What is the basic etiology of Angelman syndrome?
Loss of function of a group of genes normally expressed on the maternal chromosome 15
What syndrome is caused by a loss of function of a group of genes normally expressed on the maternal chromosome 15?
What syndrome is caused by a loss of function of a group of genes normally expressed on the paternal chromosome 15?
Angelman syndrome;
Prader-Willi syndrome
Describe the clinical features of Prader-Willi syndrome.
Neonatal hypotonia, intellectual impairment, short stature, small hands and feet, hypogonadism, behavior problems, obesity
Facial features: narrow bifrontal diameter, short upturned nose, triangular mouth, thin upper lip, almond-shaped eyes
Describe the clinical features of Angelman syndrome.
Severe intellectual impairment, seizures, ataxia, paroxysms of laughter, absent speech, wide mouth with protruding tongue, widely spaced teeth
70% of cases of Angelman syndrome are caused by a deletion of:
3-7% of cases of Angelman syndrome are caused by:
5-11% of cases of Angelman syndrome are caused by a mutation in what gene?
3% of cases of Angelman syndrome are caused by:
Genetic material on the maternal chromosome 15
Paternal uniparental disomy
UBE3A
Imprinting center defect
What is α-fetoprotein?
Is it normally found in amniotic fluid?
Fetal albumin;
no
What is a notable situation in which α-fetoprotein leaks into the amniotic fluid?
Are there others?
Neural tube defects;
yes
What is indicated by an increase in α-fetoprotein in a pregnant woman’s serum?
Potential fetal neural tube defect (or other defect)
How much folic acid should a woman be ingesting daily before and after conceiving?
How long before fertilization? How long after?
400 μg;
1 month before — through the first trimester (at least)
At how many menstrual weeks does the neural tube close?
6
A healthy woman presents at clinic indicating that she and her husband are trying to get pregnant. They have one son, who was born with a neural tube defect.
What do you recommend?
What is the risk of large doses of the substance you recommend?
Counseling + larger doses of folic acid (2-4 mg)
masking B12 deficiencies
What are the substances checked in a quad screen?
Maternal serum metabolites:
α-fetoprotein, estriols, β-HCG, inhibin A
When is a quadruple screen useful?
2nd Trimester
Values are predictive at 15-to-20 weeks of gestation
(accurate gestational age is essential)
True/False.
The quad screening is only useful in the third trimester.
False.
The quad screening is meant to be given in the second trimester.
Interpret the following quadruple screen results:
α-fetoprotein — decreased
estriols — decreased
β-HCG — increased
inhibin A — increased
Down syndrome
Interpret the following quadruple screen results:
α-fetoprotein — decreased
estriols — decreased
β-HCG — decreased
inhibin A — unchanged
Trisomy 18 (Edward’s syndrome)
Are all 4 maternal serum metabolites in a quadruple screen necessary for diagnosing neural tube defects?
No;
just α-fetoprotein (increased)
List the expected quadruple screen results for a woman carrying a fetus with Down syndrome (trisomy 21).
α-fetoprotein — decreased
Estriols — decreased
β-HCG — increased
Inhibin A — increased
List the expected quadruple screen results for a woman carrying a fetus with Edward’s syndrome (trisomy 18).
α-fetoprotein — decreased
Estriols — decreased
β-HCG — decreased
Inhibin A — unchanged
List the expected quadruple screen results for a woman carrying a fetus with neural tube defect.
α-fetoprotein — increased
Estriols — n/a
β-HCG — n/a
Inhibin A — n/a
True/False.
A quadruple screen measures fetal serum levels of the following four metabolites:
α-fetoprotein, estriols, β-HCG, inhibin A
False.
A quadruple screen measures maternal serum levels of the following four metabolites:
α-fetoprotein, estriols, β-HCG, inhibin A
Are false positives common in a quadruple screen?
What is the sensitivity for trisomy 21 and trisomy 18?
Not very (~4%);
~75%
(90% for neural tube defects)
List a few techniques via which fetal samples can be obtained for genetic analysis.
Amniocentesis
Chorionic villus sampling
Fetal blood sampling
When can amniocentesis be done for genetic analysis?
Are there any contraindications?
After 15 weeks gestation;
anhydramnios, certain infections
When is chorionic villus sampling performed (if necessary)?
Are there any contraindications?
Between weeks 10 - 13 of gestation;
cervical infections
When can fetal blood sampling be performed?
After 20 weeks
When is it best to perform a fetal ultrasound checking for abnormalities?
Weeks 18 - 20
Combined use of the triple screen and detailed ultrasound detects about __% of Down syndrome.
75
What are some potential indications for a ‘genetic ultrasound’ during pregnancy?
- Advanced maternal age
- Abnormal maternal metabolite screening
- Family history of specific disorder
- Teratogen exposure
(among others)
When is the ‘first screening’ of pregnancy?
What three portions does it entail?
Does it check for neural tube defects?
Mid-to-late 1st trimester;
(1) nuchal translucency measurement, (2) free β-HCG, (3) pregnancy-associated plasma protein;
no (only maternal α-fetoprotein in the 2nd trimester)
If the first screening of pregnancy shows abnormalities, what happens next?
A sequential (integrated) screening in the 2nd trimester;
may include chorionic villus sampling + a quad screen
What is ‘cell free fetal DNA’?
A newer screening test involving analysis of fetal chromosomal fragments in maternal blood
(99% sensitive for trisomy 21 and 18);
done after 10 weeks gestation
What are some fetal conditions that might show an increased nuchal translucency?
Trisomy 13, 18, and 21;
Turner’s syndrome;
complex congenital heart disease;
other genetic disorders
What are the main 5 infectious diseases that are teratogenic to fetal development?
TTORCH
Treponema pallidum
Toxoplasmosis
Rubella
CMV
Herpes
What is the clinical presentation of a fetus carried to term by a women infected with Zika virus?
Microcephaly,
intracranial abnormalities,
brain calcifications
What type of virus is the Zika virus?
A flavivirus
What is the incidence of toxoplasmosis infection among pregnant women?
0.5%
True/False.
On toxoplasmosis: most congenitally infected newborns are asymptomatic at birth.
True.
What is the more common presentation for a newborn that was infected with toxoplasma gondii in the uterus?
Chorioretinitis
List some of the various effects of toxoplasma gondii on a fetus in the 1st trimester.
Microcephaly, chorioretinitis, SGA, brain calcifications;
hepatosplenomegaly, rash, lymphadenopathy, jaundice;
fever, pneumonia
True/False.
Maternal infection with toxoplasma gondii in the 3rd trimester is associated with increased spontaneous abortion.
False.
Maternal infection with toxoplasma gondii in the 1st trimester is associated with increased spontaneous abortion.
What infectious agent causes syphilis?
Treponema pallidum
While most are asymptomatic, what are some of the main clinical S/Sy that may be seen in a newborn infected with syphilis while in-utero?
Chorioretinitis,
deformed nails,
alopecia,
maculopapular rash that may progress to desquamation or bullae
(also, hepatosplenomegaly, jaundice, lymphadenopathy, fever)
True/False.
A fetus is susceptible to treponema pallidum infection at any stage of gestation.
What is the fetal risk if the mother has primary or secondary siphilis?
True;
50%
Describe the effects of congenital rubella infection on the eyes, heart, ears, and head.
Eyes: cataracts, glaucoma, microphthalmia, salt and pepper retinopathy
Heart: peripheral pulmonic stenosis, patent ductus arteriosus, VSD, myocarditis
Head: microcephaly, encephalitis, mental retardation
Ears: deafness
Describe the pathology of congenital rubella infection in infected fetuses.
Focal areas of tissue necrosis and cell death (i.e. aplasia or hypoplasia).
It is thought that vascular endothelial cells become infected and presumably damage tissue through embolization and altered perfusion. Affected organs have been noted to contain decreased absolute cell number and altered cell growth patterns.
What percentage of women of childbearing age have no immunity to rubella?
10%
Primary CMV infection occurs in what percentage of pregnant women? And fetuses?
1 - 2%
1 - 2%
What are the effects of CMV infections in the 1 - 2% of fetuses infected?
90% asymptomatiic;
of the 10%, most have hearing loss and mental retardation
What is the severe form of CMV-related effects on fetal development?
Microphthalmia, microcephaly, hydrocephalus, chorioretinitis, hernia, hearing loss, mental retardation, brain calicifications
What are the main effects of congenital herpes infection?
Growth retardation, microcephaly
(15% skin lesions only
- 15% CNS only (lethargy, anorexia, vomiting)*
- 70% disseminated (jaundice, purpura, RDS, shock))*
True/False.
90% of fetal herpes is due to HSV-II.
True/False.
90% of fetal herpes is due to HSV-I.
An infant delivered to a mother infected with HSV-I has a 50% chance of being infected. When would the infection occur?
During delivery
(infected birth canal)
Which of the following can cause intrauterine fetal infection?
Varicella
Hepatitis B
Toxoplasmosa gondii
Parvovirus B19
Measles
CMV
Treponema pallidum
HPV
Influenza virus
Mumps
Rhinovirus
Rubella
Enterovirus
Herpes
HIV
All of them
Name some of the factors to consider when evaluating the risk and effects of a teratogen on fetal development.
- Timing (embryonic stage?)
- Duration
- Dose
- Teratogenicity
- Access to embryo
A newborn presents with low birth weight and growth retardation.
What teratogenic substance may have been ingested by the mother?
Nicotene
What are the two main effects of nicotene on fetal development?
Retarded fetal growth –> leading to low birthweight
What are the main S/Sy of a newborn affected by fetal alcohol syndrome in terms of CNS characteristics?
CNS: mild mental retardation, microcephaly, poor coordination, hypotonia, irritability, hyperactivity
What are the main S/Sy of a newborn affected by fetal alcohol syndrome in terms of growth characteristics?
Growth deficiency: prenatal and postnatal deficiency
What are the main S/Sy of a newborn affected by fetal alcohol syndrome in terms of facial characteristics?
Facial characteristics: short palpebral fissures, short upturned nose, hypoplastic philtrum, smooth, thinned upper vermilion, hypoplastic maxilla, retrognathia, micrognathia
List some of the most commonly abused recreational drugs that are also teratogenic.
Alcohol
Nicotene
Cocaine
Heroin
Marijuana
Methadone
What ratings are used to categorize the teratogenic risk for prescription drugs?
A, B, C, D, X
What is the teratogenic risk of a prescription drug in the ‘A’ risk category?
Controlled studies in women failed to demonstrate a risk to the fetus.
What is the teratogenic risk of a prescription drug in the ‘B’ risk category?
Animal studies have not shown a risk to the fetus, but well controlled studies in pregnant women are not available
What is the teratogenic risk of a prescription drug in the ‘C’ risk category?
Either animal studies have revealed an adverse affect on the fetus, or there are no well-controlled studies in women; or studies in animals and humans are not available. (use benefit outweighs risk concept)
What is the teratogenic risk of a prescription drug in the ‘D’ risk category?
There is positive evidence of human fetal risk, but benefits in some situations may outweigh risks
What is the teratogenic risk of a prescription drug in the ‘X’ risk category?
Animal or human studies have demonstrated fetal risk and the risk outweighs any possible benefit in pregnancy. These drugs are contraindicated in pregnancy.
Animal or human studies have demonstrated fetal risk from a prescription medication, and the risk outweighs any possible benefit in pregnancy.
What is the risk category for this drug?
X
(absolutley contraindicated)
Can methotrexate or aminopterin be used during pregnancy?
Only methotrexate after the 1st trimester
Which crosses the placenta (and is teratogenic), heparin or warfarin?
Warfarin
What teratogen is associated with severe phocomelia?
Thalidomide
What is the main cause of vaginal clear cell adenocarcinoma?
In-utero diethystilbestrol (DES) exposure
What did diethystilbestrol (DES) used to be used to accomplish?
Why is it no longer used?
To prevent pregnancy loss;
- It didn’t work
- It causes vaginal clear cell adenocarcinoma
Female fetuses with what enzymatic abnormality produce an excess of androgens?
21-hydroxylase deficiency
