Clinical Aspects of Chromosome Disorders Flashcards
What features might you expect a patient to have if they were said to ‘look chromosomal’?
- Developmental delay
- Low birth weight
- Failure to thrive
- Microcephaly
- Dysmorphic face
- Ear malformations, puts
- Transverse palmar crease
- Overlapping toes
- Cerebral, cardiac, G-U malformation
Describe the possible indications for chromosome analysis.
2 or more of the following criteria:
- Developmental delay
- IUGR/Failure to thrive
- Microcephaly
- Facial dysmorphism
- Multiple congenital malformations
List the possible different types of chromosome abnormalities.
- Polyploidy (usually triploidy)
- Autosomal trisomies (21, 18, 13)
- Sex chromosome abnormalities
- Deletions/duplications/inversions/ring chromosomes
- Translocations (Robertsonian/reciprocal)
- Mosaicism
- UPD
List some of the most common chromosomal abnormalities.
- Down Syndrome (47XX or XY, +21)
- Klinefelter Syndrome (47XXY)
- Turner Syndrome (45X)
- Edward Syndrome (47XX or XY, +18)
- Patau Syndrome (47XX or XY, +13)
- Autosomal Deletion or Duplication Syndrome
What are some of the characteristic features seen in Down syndrome?
- Up-slanting palebral fissures
- Epicanthic folds
- Brachycephaly
- Small simple ears
- Large tongue
- Sandle gap toes
- Brush field spots in the iris
What is the incidence of Down syndrome?
Down syndrome occurs in about 1 in 650 births and is associated with increased maternal age.
What is down syndrome usually caused by?
Nondisjunction events at meiosis (95%). A smaller number are due to translocations (4%) and 1% are mosaic.
What percentage of individuals with Down syndrome survive to 10 years?
About 85% and survival is increasing.
What is the risk of having a child affected at Down syndrome at all ages?
1 in 650
What is the risk of a woman having a child affected with Down syndrome at 20 years of age?
1 in 1500
What is the risk of a woman having a child affected with Down syndrome at 30 years of age?
1 in 800
What is the risk of a woman having a child affected with Down syndrome at 35 years of age?
1 in 270
Which of the chromosomes are acrocentric?
13, 14, 15, 21, 22
What is the recurrence risk of Down syndrome if the mother is young and it is due to standard non-disjunction?
1% (for any chromosome abnormality)
What is the recurrence risk of Down syndrome if the mother is a 14/21 translocation carrier?
10%
What is the recurrence risk of Down syndrome if the father is a 14/21 translocation carrier?
2%
What is the recurrence risk of Down syndrome if either parent is a 21/21 translocation carrier?
100%
What are the features of Edward syndrome?
Trisomy 18. The incidence is 1 in 5,000 and this is increased with increased maternal age. Features include intra-uterine growth retardation, failure to thrive, severe mental retardation, rocker bottom feet. 90% of babies with Edward syndrome die by one year.
Describe some of the features of Patau syndrome.
Patau syndrom results from trisomy 13. The incidence is 1 in 12,000 and this is increased with increased maternal age. Individuals with Patau syndrome have severe mental retardation. About 80% of babies with Patau syndrome die by one year of age.
What are the main sex chromosome abnormalities?
- Turner syndrome - 45,X - may be mosaic with 45X/46XX, 45X/47,XXX, or 45X/46,XY
- Triple X
- Klinefelter Syndrome
- XYY
Describe Pallister-Killan Syndrome.
Pallister-Killan Syndrome is a mosaic tetrasomy of 12p. It is a sever condition characterised by:
- Profound mental retardation
- Sparse temporal hair
- Coarse face
- Thin upper lip, downturned mouth
- Low set fleshy ears
- Supernumerary nipples, caudal appendage
- Diaphragmatic defects
- May be present only in cultured fibroblasts
What features might you expect an individual with mosaicism for trisomy 14 to display?
- Pigmentation along Blashko’s lines
- Asymmetry
What microdeletion is involved in Angelman/Prader-Willi syndrome?
Angelman/Prader-Willi = 15q11-13
What microdeletion is involved in Williams Syndrome?
Williams syndrome (elastin gene) = 7q11.23
What microdeletion is involved in Velo-cardio-facial/Shprintzen Syndrome?
Velo-cardio-facial/Shprintzen Syndrome = 22q11
What microdeletion is involved in Rubinstein-Taybi Syndrome?
Rubinstein-Taybi Syndrome = 16p13.3
What microdeletion is involved in Miller-Dieker Syndrome?
Miller-Dieker Syndrome = 17p13.3
What microdeletion is involved in Smith-Magensis Syndrome?
Smith-Magensis Syndrome = 17p11.2
What microdeletion is involved in Langer-Giedion Syndrome?
Langer-Giedion Syndrome = 8q24.1
What microdeletion is involved in WAGR Syndrome?
WAGR = 11p13
List some known microdeletion syndromes.
- Angelman/Prader-Willi = 15q11-13
- Williams syndrome (elastin gene) = 7q11.23
- Velo-cardio-facial/Shprintzen Syndrome = 22q11
- Rubinstein-Taybi Syndrome = 16p13.3
- Miller-Dieker Syndrome = 17p13.3
- Smith-Magensis Syndrome = 17p11.2
- Langer-Giedion Syndrome = 8q24.1
- WAGR = 11p13
- 1p36 deletion
How might you test for a microdeletion syndrome?
Using FISH probes.
Describe the features of Williams syndrome.
Williams syndrome involves an Elastin gene deletion at 7q11 in 90% of patients. Individuals may present with the following:
- Feeding problems
- Hypercalcaemia
- Heart defects such as supravalvular aortic stenosis and multiple peripheral pulmonary artery stenosis
- Full cheeks, stellate iris pattern
- Dev delay, cocktail party manner
- Growth retardation
- Renal abnormalities
Describe the features of Velo-Cardio-Facial Syndrome (Shprintzen Syndrome).
- 22q11 deletion which can be detected using FISH.
- Features include cleft palate, nasal voice, prominant nose with bulbous tip, almond shaped eyes, round ears with overfolded helices and long fingers and toes.
- Outflow tract heart defects including Fallot’s and truncus/coarctation.
- Mild mental retardation/psychosis
Describe the features of Smith-Magenis syndrome.
Smith-Magenis syndrome involves the deletion of 17p11.2. The features include the following:
- Dev delay, especially speech, hoarse voice.
- Behavioural problems, self-destructive, self-hugging.
- Sleep disorder, absent REM sleep.
- Short stature, small hands and feet.
- Brachycephaly, broad square face, heavy brows with lateral extension, USPF, fleshy central upper lip.
- Scoliosis, deafness, strabismus, myopia, heart defects, GU malf, hypothyroidism, immune deformation.
What percentage of mental retardation is thought to be due to cryptic telomeric translocations?
6% of unexplained mental retardation is due to a cryptic telomeric rearrangement. Multi probe system allows for testing of each telomere using FISH.
Describe the features of 1p36.3 deletion syndrome.
- Retarded growth and development
- Deep-set eyes, neat horizontal eyebrows
- Cleft lip and palate
- Microcephaly
- Delayed fontanelle closure
- Severe mental retardation, epilepsy, cerebral atrophy
- Congenital heart disease including Ebstein anomaly and cardiomyopathy
What has superseded FISH testing for some micro deletion syndromes?
Microarray analysis has replaced many forms of chromosome testing. This testing essentially sweeps the entire genome for DNA chunks that are either missing or have been duplicated (copy number variation).
A benefit over FISH is that the use of arrays requires no prior knowledge of the case and/or chromosomal region of interest.
Currently this picks up abnormalities in around 20% of those with normal karyotype who fulfil testing criteria.
As technology improves this figure is likely to increase.
What are the selection criteria used to select which patients should be selected for genetic testing for chromosomal abnormalities?
Patients are currently selected by Clinical Geneticists but testing is likely to become more mainstream.
Selection criteria include:
- Unexplained developmental delay or learning difficulties of at least moderate severity and…
- Facial dysmorphism and/or….
- Growth problems or….
- One or more major congenital abnormality or….
- Behaviour problems such as autism.
How does array CGH distinguish duplications from deletions?
- Equal hybridisation gives 1:1 ratio of ret to green.
- Deletion gives excess of control DNA sample colour.
- Duplication gives excess of patient DNA sample colour.
- If the green/red ratios are plotted, equal hybridisation will be 1.0, ratios indicating reduced patient DNA will fall between 0 and 1.0, whilst ratios showing excess patient DNA will be greater than 1.0 (and potentially could be 3 for trisomic/monosomic, or even higher). This means that the plot is asymmetrical.
What is the risk of a woman having a child affected with Down syndrome at 40 years of age?
1 in 100.
What is the risk of a woman having a child affected with Down syndrome at 45 years of age?
1 in 50 or greater.
