Unit 7 - Numerical and Structural Abnormalities

Question 1

where is triploidy and tetraploidy found in humans? what causes it?

Answer 1

spontaneous abortus tissues; not compatible with life

• 3N due to failure in gametogenesis of one of the meiotic divisions (2N gamete + 1N gamete) OR dispermy (partial hyatidiform mole)
• 4N is post meiotic event, presenting as duplication of a diploid complement (XXXX or XXYY) due to failure of early mitotic division in zygote

Question 2

what is aneuploidy? are they compatible with life? how do they arise?

Answer 2

gain or loss of Xm equaling less than one complete complement

• trisomy or monosomy
• usually incompatible with life and terminate spontaneously
• -only viable monosomy is of X Xm (45,X)
• not usually inherited, but of meiotic or mitotic nondisjunction errors

Question 3

what are Patau syndrome symptoms?

Answer 3

trisomy 13 - 1:4000 to 1:10,000

• failure to thrive, heart defect
• bilateral cleft lip/palate
• Rocker bottom feet, polydactyly
• punched out scalp (missing hair, grows back), small head

Question 4

what is mosiacism? how does it arise?

Answer 4

presence of at least 2 different cell lines with at least one clear variation between them

• numerical change (45,X/46,XX) or structural change (one cell line with a translocation that doesn’t occur in the other)
• mosaicism is acquired - it’s not inherited (so not zygotes)

Question 5

how does a mosaic differ from a chimera?

Answer 5

mosaics have at least one clear variation between the 2 different cell lines, but chimeras have many differences that can be traced back to the original two cells that fused

Question 6

what are the 3 viable autosomal trisomies? which of these has a better lifespan outlook?

Answer 6

Down syndrome - trisomy 21 - best lifespan outlook
Patau syndrome - trisomy 13
Edwards syndrome - trisomy 18

Question 7

what are Down syndrome symptoms and defects?

Answer 7

trisomy 21 - 1/700 live births

• short stature, low set ears, up slanting eyes, eye folds, short hands, protruding tongue
• microencephaly, mental retardation, increased Alzheimer disease
• usually infertile, but if viable will rarely transmit Down syndrome to offspring
• heart, lung, brain defects
• increased susceptibility to infectious disease
• increased risk of leukemia

Question 8

what are Edwards syndrome symptoms and defects?

Answer 8

trisomy 18 - 1/8000 life births

• low birth weight
• small mouth/jaw, receding chin
• ventricular septal defect
• hypoplasia of muscles
• prominent occiput
• low-set malformed ears
• Rocker bottom feet
• crossed fingers in unusual hand sign

Question 9

what is the XXX female?

Answer 9

1/1000 female live births

• due to maternal meiosis I error
• average to tall stature
• learning deficit posible
• some fertility problems, not not very common

Question 10

what is the XYY male?

Answer 10

1/1000 male births

• failure of paternal meiosis (nondisjunction error)
• tall stature
• normal intelligence and fertility
• clinically indistinguishable from 46,XY

Question 11

what is Klinefelter syndrome?

Answer 11

47,XXY - 1/1000 male life births

• 50% due to meiosis I error in father
• tall stature
• infertility
• learning deficit possible
• some female characteristics develop (extra fat on hips, breast development)

Question 12

what is Turner syndrome? symptoms?

Answer 12

45,X - 1/5000 live female births

• short stature
• webbed neck (in utero –> cystic hygroma)
• at birth, edema of hands and feet; after birth, short hands and fingers
• heart and renal anomalies
• increased carrying angle of elbow (cubitus valgus)
• shield chest
• low posterior hairline
• usually normal intelligence, but may have learning difficulties
• gonadal dysgenesis, primarily amenorrhea; usually (but not always) infertile

Question 13

how does Turner syndrome come about?

Answer 13

• half of patients have 45,X karyotype
• 15% have deletions or rearrangements of X
• 10% are mosaics (45,X/46,XX or 45,X/46,XY)

Question 14

why are Turner syndrome individuals with 45,X/46,XY mosaicism important?

Answer 14

male phenotype usually okay, but if female will have increased risk of gonadoblastoma (lethal gonadal tumor)
-recommend removal of gonads

Question 15

what is an XY female?

Answer 15

1/20,000 live births

• mutation of androgen receptor gene located on long arm of X Xm causes androgen insensitivity
• phenotypically normal female with testes
• infertile due to lack of functional internal genetalia (blind vagina and testes in abdomen or inguinal canal)

Question 16

what is an XX “male” VS an XX male?

Answer 16

“male” - congenital adrenal hyperplasia from lack of 21-hydroxylase

• normal biosynthetic pathway blocked and androgens accumulate in the female fetus
• in utero exposure causes virulization (male appearance)
• -normal ovaries and internal genitalia
• -ambiguous external genitalia
• can be due to CAH in mother or fetus

male - 1/20,000; X-Y recombination near psuedoautosomal region
-usually normal, possible Klinefelter phenotype

Question 17

what is the “opposite” of an XX male?

Answer 17

-reciprocal translocation (TDF/SRY) replaced by Xp material transmitted to a child causes Turner female phenotype with apparent 46,XY karyotype

Question 18

46,XY disorder of sex development

Answer 18

ambiguous genitalia with mild-severe penoscrotal hypospadias with or without chordee

• dysgenetic testes
• reduced to no sperm production
• Mullerian structures that range from absent to presence of fully developed uterus and fallopian tubes

Question 19

46,XY complete gonadal dysgenesis

Answer 19

“female”, TUrner features

• normal female external genitalia
• completely underdeveloped (streak) gonads
• no sperm or egg production
• presence of normal Mullerian structures

Question 20

balanced VS unbalanced structural abnormalities

Answer 20

balanced - all the material is present, but rearranged

unbalanced - some of the material is missing or duplicated

Question 21

terminal VS interstitial deletions, and what these cause? large VS small deletions?

Answer 21

terminal - distal end of one arm of an Xm is lost (requires only 1 break)
interstitial - internal region of Xm is lost (requires 2 breaks)
-leads to partial monosomy
-size is not as important as which genes and how many are missing
-small deletions may be tolerated with minimal clinical abnormalities
-large deletions are associated with developmental delay, mental retardation, abnormal features

Question 22

Wolf-Hirschhorn Syndrome and symptoms

Answer 22

4p- syndrome (terminal deletion of short arm of Xm 4)

• microcephaly, micrognathia, epicanthal folds, “startled” expression, arched brows, long nose with squared off end (look like a Greek warrior helmet)
• hypotonia, short stature, developmental delay
• increased risk for seizures

Question 23

terminal VS interstitial duplications, and what these cause?

Answer 23

• terminal - extra material at one end of the Xm (usually direct duplication of material adjacent to it)
• interstitial - extra DNA within an Xm; usually a copy of adjacent regions
• usually sporadic, but may be inherited from a parent with a benign Xm rearrangement
• the larger the duplicated piece, the more severe the abnormalities

Question 24

what is Cornelia de Lange syndrome?

Answer 24

no longer associated with duplications of long arm of Xm 3

• short, hirsute, missing distal arms and/or legs, unibrow
• developmentally delayed
• look more similar to other patients than own family

Question 25

reciprocal translocations (balanced)

Answer 25

equal exchange involving two+ nonhomologous Xm

• each Xm breaks once and the pieces exchange, producing 2+ derivative Xm
• balanced - all of DNA is retained, and pieces are moved to a new location (as long as breaks don’t occur in important coding gene, rearrangement is benign in person, but offspring may have Xmal abnormalities)

Question 26

balanced VS unbalanced translocations

Answer 26

balanced gametes: alternate segregation; there is either no rearrangement, or balanced translocation

unbalanced gametes - 1/3 of the time have gain or loss of material

• adjacent 1 segregation: duplication and deletion of gene regions (gametes will have too much of one type of Xmal info)
• adjacent 2 segregation: homologous centromeres move to same poles (very rare)
• 3:1 segregation: 3 Xm in one gamete and 1 in the other

Question 27

what is the significance of a balanced translocation?

Answer 27

individual issues, and 1:500 (quite common)

• carriers phenotypically normal
• increased risk that another pregnancy will have an unbalanced Xmal complement
• increased risk of infertility or spontaneous fetal loss
• increased risk of abnormal live born (10% per pregnancy)
• translocations can be inherited (other members of family may have rearrangement) or de novo (if detected prenatally, may not be able to tell if it’s balanced or not)

Question 28

what is a Robertsonian translocation?

Answer 28

variant of standard reciprocal translocation; centromere to centromere translocation involving acrocentric Xm

• may be between nonhomologous or homologous Xm
• results in loss of both short arms (repeat copies of rRNA), but since this material is on remaining 8 acrocentric Xm, the loss is not deleterious

Question 29

when is a Robertsonian transloccation deleterious or not?

Answer 29

carrier has 45 Xm (due to Xmal fusion), but confers no known clinical problems
-will negatively impact meiosis, causing nondisjunction errors that transmit to offspring

Question 30

how can Robertsonian translocations cause trisomy 13 and trisomy 21?

Answer 30

Patau: child inherits 13,14, 14 from mother, and 13, 14 from father
Down: child gets 21,21 from one parent, and 21 from other

Question 31

pericentric VS paracentric inversion, and respective inversion loops

Answer 31

reversal of an Xmal segment with respect to the normal gene arrangement

• peri: break occurs on opposite sides of centromere, so centromere changes and Xm morphology may change
• -larger inversion has more viable gametes b/c reduces duplication/deletion errors
• -smaller inversion loops have greater risk of unbalanced gametes
• para: breaks occur on same arm of centromere, so not involved in rearrangement
• -apparent suppression of recombination because recombinant products (dicentric and acentric) have been deleted