Flashcards in Genetic and Chromosomal Disorders Deck (15)
What is the most common sex chromosome disorder in females? How many chromosomes do these patients have? What physical characteristics do they present with? What is this syndrome the most common cause of?
- Turner syndrome (XO); patients are female and are missing an X chromosome, they have 45 chromosomes
- patients present with short stature, shield chest, webbed neck and swollen hands/feet (the last two are due to abnormalities with lymphatics)
- patients also have short 4th digits, leading to the "knuckle-knuckle-dimple-knuckle" sign
- patients have NORMAL intelligence
- Turner syndrome is the most common cause of primary amenorrhea (this is because the ovaries undergo dysgensis, called streak ovaries, and get replaced with fibrous tissue)
- note that the vast majority of cases do spontaneously abort
What structural defects do patients with Turner syndrome commonly have? Is the syndrome more commonly due to complete monosomy or mosaicism?
- Turner syndrome is highly associated with bicuspid aortic valve, preductal coarctation, and horseshoe kidney
- most cases are due to mosaicism
Why are patients with Turner syndrome of a short stature?
- this is because they only have one X chromosome, which contains the SHOX gene needed for growth
- although most genes in XX patients are only active in one copy (the other being a Barr body), the SHOX gene is unique in that both copies are active in a normal person (so 2 active SHOX genes are needed for normal growth)
What is the most common sex chromosome disorder in males? How many chromosomes do these patients have? What physical characteristics do they present with? What is this syndrome a major cause of?
- Klinefelter syndrome (XXY); patients are male with an extra X chromosome (Barr body is present), they have 47 chromosomes
- patients present with testicular atrophy, eunuchoid body shape, gynecomastia, female hair distribution, and are tall with long extremities
- Klinefelter syndrome is a major cause of hypogonadism/male infertility and also increases the risk for testicular cancer (it usually presents at puberty or pursuit of infertility)
What is nondisjunction and when during gamete formation can it occur? What gametes result from nondisjunction?
- nondisjunction occurs during meiosis (gamete formation) and is when a chromosome fails to split and enter 2 different daughter cells (so both pairs enter 1 cell instead)
- can occur during meiosis I or II
- in meiosis I: will result in 1 daughter cell with both copies of the homologous chromosomes and 1 daughter cell with no copies of that chromosome; meiosis II will then yield 2 gametes with an extra chromosome (these contain 2 homologous chromatids) and 2 gametes with one less chromosome; results in heterodisomy (the aneuploid chromosomes are not identical)
- in meiosis II: will result in 1 gamete with an extra chromosome (contains 2 sister chromatids), 1 gamete with one less chromosome; the other 2 gametes will be normal (each has 1 chromatid); results in isodisomy (the aneuploid chromosomes are identical)
What are the autosomal trisomies? How common is each? Which is the most common?
- trisomy 21 (Down syndrome): 1:700
- trisomy 18 (Edwards syndrome): 1:8,000
- trisomy 13 (Patau syndrome): 1:15,000
- (trisomy 16 is the MOST common trisomy, but it is not viable, where as the other 3 are - even if just for a year)
What is Down syndrome? What findings are associated with it?
- Down syndrome is trisomy 21 (an autosomal trisomy)
- it is the MOST common viable chromosomal disorder and is also the MOST common cause of genetic intellectual disability
- findings: intellectual disability, flat facies, up slanting palpebral fissures, large tongue, small ears, single palmar crease (called a Simian crease), duodenal atresia, Hirschsprung disease, septal defects
What do patients with Down syndrome have an increased risk of developing? What are the major factors contributing to these patients survival? What are the ways Down syndrome can occur?
- patients are at an increased risk of developing leukemia
- nearly all patients will also develop early-onset Alzheimer's (usually by the time they are 35)
- congenital heart defects are the major contributing factor decreased survival in younger patients, while Alzheimer's is the main factor for older patients
- 95% of cases are due to meiotic nondisjunction (47 chromosomes)
- 4% of cases are due to Robertsonian translocation (46)
- 1% of cases are due to mosaicism (46)
What is the major risk factor for Down syndrome?
- major risk factor is maternal age (incidence of Down syndrome is 1:1500 at age 20 and 1:25 at 45)
Explain how a patient with a Robertsonian translocation can have a child with Down syndrome.
- Robertsonian translocations are nonreciprocal translocations between the acrocentric chromosomes (13, 14, 15, 21, and 22); the long arms of two chromosomes fuse together (the separated short arms are eventually lost) to form a "single" chromosome made up of two chromosomes
- a common Robertsonian translocation occurs between chromosomes 14 and 21; if the child inherits this abnormal chromosome, it will inherit the attached 21 as well (so it will be getting the 14:21 and a 21 from one parent and a 14 and 21 from the other)
- children with Down syndrome from this mechanism therefore have the normal number of 46 chromosomes (but one of their chromosome 14's has the attached extra 21)
- "carriers" will actually have 45 chromosomes, but the genetic material is still there and will therefore have no symptoms
What is the probability that a parent "carrier" for Down syndrome (via a Roberstonian translocation) will have a child with Down syndrome? (Assume the partner is normal.)
- the Robertsonian translocation results in the potential for that parent to form 6 different gametes
- 1/6 of children will be normal (normal gamete)
- 1/6 will inherit the 14:21 translocation, but will be balanced (the gamete with only the 14:21 chromosome) these children will also be "carriers"
- 1/6 will be trisomy 14 (the gamete with 14:21 and 14); not viable
- 1/6 will be trisomy 21 (the gamete with 14:21 and 21)
- 1/6 will be monosomy 14 (the gamete with only 21); not viable
- 1/6 will be monosomy 21 (the gamete with only 14); not viable
What is Edwards syndrome? What findings are associated with it?
- Edwards syndrome is trisomy 18 (an autosomal trisomy)
- findings: severe intellectual disability, rocker-bottom feet, clenched hands with overlapping fingers, congenital heart disease
- patients usually die within 1 year of birth
What is Patau syndrome? What findings are associated with it?
- Patau syndrome is trisomy 13 (an autosomal trisomy)
- findings: severe intellectual disability, rocker-bottom feet, cleft lip and palate, polydactyly, congenital heart disease
- patients usually die within 1 year of birth
What are relative levels of alpha-fetoprotein, beta-hCG, unconjugated estriol, and inhibin A that occur in each of the autosomal trisomies?
- Down (21): low AFP, high beta-hCG, low estriol, high inhibin
- Edwards (18): low AFP, low beta-hCG, low estriol, normal/low inhibin
- Patau (13): normal AFP, low beta-hCG, (unknown estriol), normal inhibin