Genetics I Flashcards
What is a Robertsonian translocation? [1]
When a person has a Robertsonian translocation, they loose the short arm completely, and the two long arms connect to each other at the centromere, essentially loosing a chromosome when they get rid of the two short arms.
- In this scenario the person is usually phenotypically normal, but has 45 chromosomes when counted and has a risk of problems in their offspring.
Which trisomys are the most common and which is the extra chromosome/ [3]
Patau syndrome:
- This is trisomy 13. The syndrome varies in severity. Patients have dysmorphic features, structural abnormalities affecting almost all areas of their body and learning disability. They have characteristic “rocker bottom feet”, where the soles of the feet are convex (rounded outwards) in shape. Look out for rocker bottom feet in exams.
Edwards syndrome:
- This is trisomy 18. The syndrome varies in severity and affects almost all areas of the body, resulting in dysmorphic features and learning disability. They also have “rocker bottom feet”.
Down’s syndrome: This is trisomy 21.
Describe what is meant by mosaicism [1]
Mosaicism is an interesting scenario where the chromosomal abnormality actually happens after conception. The abnormality occurs in a portion of cells in the body and not in others.
Describe the features of DS
Hypotonia (reduced muscle tone)
Brachycephaly (small head with a flat back)
Short neck
Short stature
Flattened face and nose
Prominent epicanthic folds
- are folds of skin covering the medial portion of the eye and eyelid.
Upward sloping palpebral fissures
- gaps between the lower and upper eyelid.
Single palmar crease
State the complications that DS people are at risk of [9]
Learning disability
Hirschsprung’s disease
Recurrent otitis media
Deafness.
- Eustachian tube abnormalities lead to glue ear and conductive hearing loss
repeated respiratory infections (+hearing impairment from glue ear)
Visual problems
- such myopia, strabismus and cataracts
Hypothyroidism occurs in 10 – 20%
Cardiac defects
- affect 1 in 3, particularly ASD, VSD, patent ductus arteriosus and tetralogy of Fallot
Atlantoaxial instability
Leukaemia is more common in children with Down’s
Dementia is more common in adults with Down’s
Describe the specific cardiac problems seen in Down’s syndrome [5]
endocardial cushion defect (most common, 40%, also known as atrioventricular septal canal defects)
ventricular septal defect (c. 30%)
secundum atrial septal defect (c. 10%)
tetralogy of Fallot (c. 5%)
isolated patent ductus arteriosus (c. 5%)
Which visual problems are DS people more at risk of ?
strabismus
cataracts: congenital and acquired are both more common
recurrent blepharitis
glaucoma
What are the regular routine follow up investigations would need for DS? [4]
There are some routine follow up investigations that are important for children with Down’s syndrome:
Regular thyroid checks (2 yearly)
Echocardiogram to diagnose cardiac defects
Regular audiometry for hearing impairment
Regular eye checks
Klinefelter’s syndrome is associated with which karyotype? [1]
Klinefelter’s syndrome is associated with karyotype 47, XXY.
Characteristic features of Klinefelter’s? [6]
- Often taller than average
- Lack of secondary sexual characteristics
- Small, firm testes
- Infertile
- Gynaecomastia - increased incidence of breast cancer
- Elevated gonadotrophin levels but low testosterone
There is no way to treat the underlying genetic cause of Klinefelter syndrome. Treatment aims to help with the features of the condition
What are these treatments? [3]
Testosterone injections improve many of the symptoms
Advanced IVF techniques have the potential to allow fertility
Breast reduction surgery for cosmetic purposes
Klinefelter’s have an increased risk of which conditions? [4]
Breast cancer compared with other males (but still less than females)
Osteoporosis
Diabetes
Anxiety and depression
TOMTIP:
- The three classic features to remember and look out for in exams for Tuner’s syndrome are [3]
TOM TIP: The three classic features to remember and look out for in exams are short stature, webbed neck and widely spaced nipples.
What are the features of Turner syndrome? [+]
- Short stature
- Webbed neck
- High arching palate
- Downward sloping eyes with ptosis
- Broad chest with widely spaced nipples
- Cubitus valgus
- Underdeveloped ovaries with reduced function
- Late or incomplete puberty
- Most women are infertile
- Cubitus valgus refers to an abnormal feature of the elbow. When the arm is extended downwards with the palms facing forward, the angle of the forearm at the elbow is exaggerated, angled away from the body.
What are associated conditions of Turner syndrome? [+]
Recurrent otitis media
Recurrent urinary tract infections
Coarctation of the aorta
Hypothyroidism
Hypertension
Obesity
Diabetes
Osteoporosis
Various specific learning disabilities
There is no way to treat the underlying genetic cause of Turner syndrome.
Treatment aims to help with the symptoms of the condition.
What are the treatments? [3]
Growth hormone therapy
- initiated at diagnosis
- can be used to prevent short stature
- It should be continued until final adult height is reached.
Oestrogen and progesterone
- replacement can help establish female secondary sex characteristics, regulate the menstrual cycle and prevent osteoporosis
- should be initiated around the age of pubertal onset (around 12 years)
- Progestin is added once breakthrough bleeding occurs or after 2 years of oestrogen therapy to induce regular menses and prevent endometrial hyperplasia.
Fertility treatment can increase the chances of becoming pregnant
Patients need monitoring for the associated conditions and complications. Treatable conditions such as hypertension and hypothyroidism should be managed appropriate.
what are the first line investigations for Turner’s syndrome? [2]
Karyotyping:
- This is the gold standard for diagnosing Turner’s syndrome. It involves analysing the number and structure of chromosomes in a sample of cells. In Turner’s syndrome, one complete or partial X chromosome is missing.
FISH (Fluorescence in situ hybridisation)
- This technique can be used to confirm the diagnosis if karyotyping results are inconclusive. FISH allows visualisation of specific DNA sequences on chromosomes using fluorescent probes, thereby identifying any chromosomal abnormalities.
What are common kidney problems in Turner syndrome patients [2]
These can include horseshoe kidney or unilateral renal agenesis.
Which cardiac problems are associated with Turner’s syndrome [2]
coarctation of the aorta or bicuspid aortic valve
Turner’s syndrome:
Hypertension should be managed aggressively due to increased risk of []
Hypertension should be managed aggressively due to increased risk of aortic dissection.
How should skeletal health be managed in Turner’s syndrome? [2]
Dual-energy X-ray absorptiometry (DEXA) scanning should be performed at baseline when oestrogen replacement is initiated and periodically thereafter to monitor bone health.
Vitamin D and calcium supplementation may be necessary if dietary intake is insufficient or in the presence of osteoporosis/osteopenia.
Musculoskeletal Complications in Turner’s syndrome? [1]
Scoliosis/Kyphosis: Up to 25% of individuals are affected by these conditions which can cause back pain and breathing difficulties if severe.
Describe the features of Noonan syndrome [+]
Often thought of as the ‘male Turner’s’, Noonan syndrome is an autosomal dominant condition associated with a normal karyotype. It is thought to be caused by a defect in a gene on chromosome 12
Short stature
Broad forehead
Downward sloping eyes with ptosis
Hypertelorism (wide space between the eyes)
Prominent nasolabial folds
Low set ears
Webbed neck
Widely spaced nipples
PM
Noonan syndrome:
* As well as features similar to Turner’s syndrome (webbed neck, widely-spaced nipples, short stature, pectus carinatum and excavatum), a number of characteristic clinical signs may also be seen, such as [5]
cardiac:
- pulmonary valve stenosis
ptosis
triangular-shaped face
low-set ears
coagulation problems: factor XI deficiency
Which cardiac complications are associated with Noonan’s syndrome? [3]
Congenital heart disease, particularly pulmonary valve stenosis, hypertrophic cardiomyopathy and ASD
Noonan syndrome has increased risk of which malignancies? [2]
Increased risk of leukaemia and neuroblastoma
Marfan’s syndrome is an autosomal dominant connective tissue disorder. It is caused by a defect in the [] gene on chromosome 15 that codes for the protein [] It affects around 1 in 3,000 people.
Marfan’s syndrome is an autosomal dominant connective tissue disorder. It is caused by a defect in the FBN1 gene on chromosome 15 that codes for the protein fibrillin-1. It affects around 1 in 3,000 people.
Describe the features of Marfan’s syndrome:
- general [5]
- cardiac [4]
- lungs [1]
- eyes [3]
tall stature with arm span to height ratio > 1.05
high-arched palate
arachnodactyly
pectus excavatum
pes planus
scoliosis of > 20 degrees
heart:
* dilation of the aortic sinuses (seen in 90%) which may lead to aortic aneurysm, aortic dissection, aortic regurgitation
* mitral valve prolapse (75%),
lungs:
- repeated pneumothoraces
eyes:
upwards lens dislocation (superotemporal ectopia lentis)
blue sclera
myopia
dural ectasia (ballooning of the dural sac at the lumbosacral level)
TOM TIP: Marfan syndrome is a favourite for OSCE exams. If you meet a patient in your OSCE that appears [], has [] or a murmur suggestive of mitral or aortic [], think of Marfan syndrome.
TOM TIP: Marfan syndrome is a favourite for OSCE exams. If you meet a patient in your OSCE that appears tall, has hypermobility or a murmur suggestive of mitral or aortic regurgitation, think of Marfan syndrome.
You can really impress you’re examiners by going on to examine for other features of the condition, such as looking in the mouth for a high arch palate, checking the arm span, looking for arachnodactyly and testing for hypermobility.
Marfans:
- The greatest risk is from the associated cardiac complications, particularly [2].
Where these complications occur they may require surgical correction.
The greatest risk is from the associated cardiac complications, particularly valve prolapse and aortic aneurysms.
Where these complications occur they may require surgical correction.
Describe the main aim of management in Marfans and how this is achieved? [3]
The aim of management is to minimise the blood pressure and heart rate to minimise the stress on the heart and the risk of complications developing.
- This is achieved by lifestyle changes, such as avoiding intense exercise and avoiding caffeine and other stimulants.
- Preventative medications such as beta blockers and angiotensin II receptor antagonists can also help reduce the risk of complications.
What are pregnant Marfan’s patients at a high risk of developing? [1]
Pregnancy has to be carefully considered, as it carries a significant risk of developing aortic aneurysms and associated complications.
Marfan’s syndrome - mitral valve prolapse
Marfan’s syndrome - defect in the fibrillin-1 gene
Marfan’s syndrome - dilation of the aortic sinuses
Tall, long fingered, aortic pathology, pneumothoraces - Marfan’s syndrome
Secundum atrial septal defect
Isolated patent ductus arteriosus
endocardial cushion defect
Recurrent chest infections
Duodenal atresia
Upslanting palpebral fissures
Primary amenorrhoea
Elevated gonadotrophin levels
Turner’s syndrome - coarctation of the aorta
Turner’s syndrome - bicuspid aortic valve
Turner’s syndrome - lymphoedema in neonates
a young boy is noted to have a webbed neck, pulmonary stenosis, ptosis and short stature. The karyotype is normal
