20.04.16 Sex chromosome aneuplodies Flashcards
1
Q
What is genetics associated with Klinefelter syndrome?
A
- XXY
2
Q
Klinefelter syndrome - common symptoms
A
- many show no symptoms apart from infertility
- most common cause of hypogonadism in males (small testes)
- reduced fertility/infertility
- reduced testosterone/endocrine function
- tall
- gynecomastia
- some mild LD/DD
3
Q
Klinefelter syndrome - what is the recurrence risk?
A
- not increased above general population
4
Q
Klinefelter syndrome - standard testing
A
- karyotyping
- 10% cases by prenatal diagnosis
- 25% at puberty
- diagnosis often accidentally as 64 % individuals not recognized as such
5
Q
Klinefelter syndrome - do you get mosaicism?
A
- Yes - 47,XXY/46,XY with varying degrees of spermatogenic failure
- 47,XXY/46,XX with clinical features suggesting Klinefelter syndrome are very rare
- 85% cases are mosaic (25% have sperm present)
6
Q
Klinefelter syndrome - what is the molecular mechanism?
A
- Nondisjunction of one X during meiosis I in the male or meiosis II in the female
- No parent of origin effect reported
- Maternal (and possibly paternal) age is a risk factor (4-fold increase in prevalence in mothers >40years)
7
Q
What variants of Klinefelter syndrome do you get?
A
- 48,XXYY - tall, sparse body hair, small testicles, gynecomastia, hypogonasism, IQ less than 47,XXY, prone to aggressive behaviour
- 48,XXXY - tall stature with ocular hypertelorism, flat nasal bridge, fifth finger clinodactyly and small penis and testicles with hypergonadotrophic hypogonadism. They have an IQ between 40-60 with severely delayed speech.
- 49,XXXXY - extremely rare, severe phenotype. Microcephaly with short stature, ocular hypertelorism, flat nasal bridge and upsanting palpebral fissures. They may have cleft palate and heart defects. They have an IQ between 20 and 60.
- Phenotypic effects increase with number of extra X’s
- Normally caused by the extra copies of genes in PAR regions
8
Q
XYY syndrome - what is the associated phenotype?
A
- Taller than average
- Normal sexual development and are fertile
- Half will have LD, delayed speech, delayed motor skills, hypotonia
9
Q
What is the genetics of Turner syndrome?
A
- 45, X (55% of cases)
- The rest are commonly:
1) 46,X,abnormal X (~25% of cases)
2) 46,X,i(X)(q10) (~12-20% of cases)
3) Mosaic (at least) (~15% of cases)
4) 45,X/46,XX/47,XXX (~7% of cases)
5) 45,X/46,XY and 45,X/46,X, +mar (~ 6-11% of cases) - In most cases the X comes from the mother - may be due to nondisjunction in the father
10
Q
Turner symdrome - common symptoms
A
- Turner syndrome is a cause of gonadal dysfunction, primary amenorrhea, premature ovarian failure (hypergonadotropic hypogonadism), streak gonads and infertility
- short stature
- short and webbed neck
- early loss of ovarian function (ovarian hypofunction or premature ovarian failure)
- puffiness or swelling (lymphedema) of the hands and feet
- hypoplastic widely spaced nipples
- skeletal abnormalities, kidney problems, hypothyroidism
- Failure to develop secondary sex characteristics is typical
- Less common - Developmental delays, nonverbal learning disabilities, and behavioral problems are possible, although these characteristics vary among affected individuals.
11
Q
Turner syndrome - recurrence risk
A
- Normally sporadic
- Risk of recurrence is not increased for subsequent pregnancies
- Rare exceptions may include the presence of a balanced translocation of the X chromosome in a parent, or where the mother has X mosaicism restricted to her germ cells
12
Q
Turner syndrome - do you get mosaicism?
A
- Mosaicism is common
1) Normal or partly deleted Y chromosome present in 6-11% of cases - These cases have 10% to 30% risk of developing gonadoblastoma -
- Gonadectomy is recommended and mosaic cases need assessment for presence of SRY
2) Mosaic 45,X/46,XX may have a “milder” phenotype, may be taller, may enter puberty spontaneously, likely to have 2ry amenorrhea/premature menopause, may be fertile, and sometimes mosaic with 47,XXX cell line.
3) Structural mosaic: (45,X with /46,X,i(X)(q10), /46,X,r(X), /46,X,del(Xq) may show fewer of the Turner stigmata and may only show short stature and gonadal dysgenesis.
4) Mosaics with X derived markers and rings generally have classic Turner features. If Xist is absent on the marker, may have a more severe phenotype due to failure of inactivation resulting in functional disomy. Severity of phenotype will be dependent on the genes present. Small markers without Xist may not effect phenotype.
13
Q
How is Turner syndrome diagnosed?
A
1) Prenatally - 99% of Turner conceptions end in stillbirth or spontaneous abortion
2) Puberty - due to delayed puberty and short stature
14
Q
What are the important genes associated with Turner syndrome?
A
- SHOX (PAR1 region - Xp22.33;Yp11.3)
- Important for bone development and growth
- The loss of one copy of this gene likely causes short stature and skeletal abnormalities in women with Turner syndrome
- Xp11.2-p22.1 region is important in ovarian failure (gonadal dysgenesis)
- Currently thought that “gonadoblastoma” gene is localised to proximal Yq.
15
Q
Triple X syndrome - clinical phenotype
A
- Essentially normal phenotype
- tall stature, epicanthal folds, hypotonia and clinodactyly
- Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) are also associated findings.
- Children with trisomy X have higher rates of motor and speech delays
- Most individuals lead normal lives and have no difficulty getting pregnant
- However, phenotype can be very variable and this is important for genetic counselling
