Genetics Flashcards
What are features of Down’s syndrome?
Face = upslanting palpebral fissures, prominent epicanthic folds, brush field spots in iris, protruding tongue, small low set ears, flat occipital
Single palmar crease
Sandal gap
Hypotonia
What are cardiac associations with Down’s syndrome?
Ventricular septal defect
Atrial septal defect
AV septal canal defect
Tetralogy of Fallot
PDA
What are long-term complications of Down’s syndrome?
Subfertility
Short stature
Recurrent otitis media
Increased risk of ALL
Hypothyrodism
Alzheimer’s
Learning disability
What are clinical features of Klinefelter’s syndrome?
Lack of secondary sexual characteristics
Taller than average
Small testicles
Infertility
Gynaecomastia (increased risk of breast cancer)
LH and FSH = High
Are LH and FSH high or low in Klinefelter’s?
High
What are features of Turner syndrome?
Short stature
Webbed neck
Widely spaced nipples
Primary amenorrhoea
High-arched palate
Cubitus valves
Lymphoedema as a neonate (esp of feet)
What are associated conditions with Turner Syndrome?
Bicuspid aortic valve
Coarctation of the aorta
Recurrent otitis media
Recurrent UTI
What hereditary pattern does Noonan syndrome have?
Autosomal dominant
What are features of Noonan syndrome?
Short stature
Webbed neck
Widely spaced nipples
Broad forehead
Downward facing eyes
Low set ears
Triangular face
Ptosis
What conditions are associated with Noonan Syndrome?
Congenital heart disease - esp pulmonary valve stenosis
Undescended testes
Learning disability
Coagulation problems
What hereditary pattern does Marfan syndrome have?
Autosomal dominant
What are features of Marfan syndrome?
Tall stature
Long neck
Long limbs
Long fingers
High arched palate
Hyper mobility
Pectus excavatum
Pes planus (flat foot)
What conditions are associated with Marfan syndrome?
Upward lens dislocation
Dilation of aortic sinuses - can lead to aortic aneurysm/dissection/regurg
Mitral valve prolapse - can lead to mitral regurgitation
Recurrent pneumothorax
Scoliosis
Ductal ectasia
What medication can be used in Marfan syndrome to reduce morbidity/mortality?
Beta blocker or ACEi
What are features of Fragile X Syndrome? (mnemonic)
e X tra large testes, jaws, and ears”
Intellectual disability
Long thin face
Large ears
High arched palate
Large testicles
Hyper mobility
Autism/ADHD
Hypotonia
What are features of Prader-Willi Syndrome? (mnemonic)
Constant insatiable hunger leading to obesity
Hypotonia as a baby
dysmorphic features
Short stature
Hypogonadism
Learning difficulties
Almond shaped eyes
Behavioural problems
Prader: paternal imprinting, angelman: maternal imprinting
What medication can be used in Prader Willi Syndrome?
Growth hormone
What are features of Angelman Syndrome?
Delayed development
Intellectual disability
Severe delay or absence of speech develop,ent
Fascination with water
Happy demeanour
Widely spaced teeth
Inappropriate laughter
What are features of Edward’s syndrome?
Micrognathia (small lower jaw)
Low set ears
Rocker bottom feet
Overlapping of fingers
What are features of Patau syndrome?
Microcephaly
Small eyes
Cleft lip/palate
Polydactyly
Scalp lesions
What are features of William syndrome?
Broad forehead
Starburst eyes
Flattened nasal bridge
very friendly and sociable
Wide mouth - big smile
Small chin
You are consulting with a family whose son has been referred due to suspected learning difficulties. Whilst talking to his parents, you observe the son has a bubbly outgoing personality, and contemplate whether this might be a case of William’s syndrome.
What physical feature would most support this diagnosis?
A. Rocker-bottom feet
B. Flattened philtrum
C. Tall, slender stature
D. Webbing of the neck
E. Elfin facies
Answer: E, William’s syndrome - associated with elfin facies
What conditions are associated with William Syndrome?
Supravalvular aortic stenosis
Hypercalcaemia
ADHD
Hypertension
What are complications of Fragile X syndrome?
Mitral valve prolapse Pes planus Autism Memory problems Speech disorders
A couple is referred to see their doctor in a family planning clinic as they are looking to have a second child. Their first child died from Tay Sachs disease. After genetic testing, both parents are found to be heterozygous for the condition.
What is the chance their next child will be a carrier of this condition?
A. 0%
B. 25%
C. 50%
D. 50% if female 0% if male
E. 100%
C. 50%
For autosomal recessive conditions, if both parents are carriers (heterozygote) there is a 50% chance of having a carrier (heterozygote) child
A boy is noted to have a webbed neck and pectus excavatum
Noonan syndrome
An infant is found to have small eyes and polydactyly
Patau syndrome
A 7-year-old boy with learning difficulties and macrocephaly
fragile X
what inheritance is retinoblastoma?
autosomal dominant
Which of the following conditions is usually inherited in an autosomal dominant fashion?
A. Friedreich’s ataxia
B. Hurler’s syndrome
C. Phenylketonuria
D. Familial adenomatous polyposis
E. Haemochromatosis
D. Familial adenomatous polyposis
Autosomal recessive conditions are ‘metabolic’ - exceptions: inherited ataxias
Autosomal dominant conditions are ‘structural’ - exceptions: Gilbert’s, hyperlipidaemia type II
E. Haematochromatosis: autosomal recessive
The following conditions are autosomal dominant:
Achondroplasia
Acute intermittent porphyria
Adult polycystic disease
Antithrombin III deficiency
Ehlers-Danlos syndrome
Familial adenomatous polyposis
Hereditary haemorrhagic telangiectasia
Hereditary spherocytosis
Hereditary non-polyposis colorectal carcinoma
Huntington’s disease
Hyperlipidaemia type II
Hypokalaemic periodic paralysis
Malignant hyperthermia
Marfan’s syndromes
Myotonic dystrophy
Neurofibromatosis
Noonan syndrome
Osteogenesis imperfecta
Peutz-Jeghers syndrome
Retinoblastoma
Romano-Ward syndrome
tuberous sclerosis
Von Hippel-Lindau syndrome
Von Willebrand’s disease*
*type 3 von Willebrand’s disease (most severe form) is inherited as an autosomal recessive trait. Around 80% of patients have type 1 disease
You are reviewing the growth of a 4-week-old neonate. She has a length on the 35th percentile, weight on the 42nd percentile and a head circumference on the 4th percentile.
Which of the following is the most likely cause of her microcephaly?
A. Thalassaemia
B. Turner’s syndrome
C. Achondroplasia
D. Foetal alcohol syndrome
E. Cerebral palsy
D. Foetal alcohol syndrome
Foetal alcohol syndrome - associated with microcephaly
An 8-year-old boy presented with progressive gait disturbance and falls. He was first seen by a paediatric neurologist for unsteady gait and toe walking at the age of 4 years. His gait unsteadiness commenced around the age of 3 years with frequent falls. Tremors in the hands were noted sometime prior to this visit. Gait was wide-based and unsteady. Further detailed examination revealed pes cavus, mild scoliosis, and absence of cardiac murmur.
What is the inheritance pattern of the underlying condition?
A. Autosomal dominant
B. Autosomal recessive
C. Mitochondrial
D. X-lined recessive
E. X-linked dominant
B. Autosomal recessive
Friedreich’s ataxia is autosomal recessive
Friedreich’s ataxia is the most common type of hereditary ataxia. Symptoms usually first develop before the age of 25. The condition presents with ataxia, cardiomyopathy, motor weakness, pes cavus foot deformity and scoliosis.
Beckwith-Wiedemann syndrome mnemonic
A 4-year-old girl is regularly seen in clinic due to recurrent chest infections. During her first year of life, she required extensive management for failure to thrive.
A mutation present on which chromosome is responsible for her symptoms?
This child shows classical symptoms of Cystic Fibrosis (CF) with recurrent chest infections associated with failure to thrive in infancy. CF is caused by a mutation in the CFTR gene on Chromosome 7 and often manifests in the first year of life with malabsorption and failure to thrive due to pancreatic insufficiency.
The newborn blood spot screening test (Immunoreactive trypsinogen (IRT)) has allowed us to identify affected children before most symptoms are present and to initiate appropriate treatment as soon as possible.
Mutations affect the structure, processing or cellular transport of the CFTR protein (cystic fibrosis transmembrane conductance regulator)
The most common mutation, affecting Delta-F508, results in abnormal glycosylation and subsequent degradation of the CFTR protein before it reaches the cell membrane.
Defects of chloride transport (and therefore water movement by osmosis) across cell membranes cause mucous secretions in different systems to be very thick.
what main body systems does CF typically affect?
Respiratory system:
Thick mucus in the lungs causes cough, recurrent infections, and bronchiectasis.
Sinusitis and nasal polyps are also very common. Patients usually are colonised with Pseudomonas in the lung by about age 20.
Digestive system:
Reduced pancreatic lipase enzyme secretion inhibits fat absorption, causing steatorrhoea
Poor fat absorption consequently contributes to deficiency of fat-soluble vitamins (A, D, E and K)
These factors contribute to poor weight gain
Damage to the pancreas can also result in patients with cystic fibrosis developing diabetes mellitus & failure to thrive, hypoproteinaemia
-meconium ileus, rectal prolapse
Hepatic:
chronic hepatic disease/cirrhosis
Reproductive system:
Seminiferous tubes also get blocked; most men with cystic fibrosis are unable to conceive naturally (resulting in obstructive azoospermia)
Fertility is also slightly lower than average in women due to thicker cervical mucus.
how does CF present in neonates/most common test?
-As a neonate, cystic fibrosis may present acutely with meconium ileus.
-This is due to viscous meconium (from thick mucus) that causes a delay in passing meconium and even gastrointestinal obstruction.
-Meconium ileus is diagnosed and treated with a gastrograffin enema.
presentation of CF in infants/older children:
- As an infant, cystic fibrosis may present with parents commenting that the baby’s sweat is very salty - this is noticed when they kiss their baby
- Faltering growth
- Recurrent chest infections
- toddlers: Malabsorption syndromes
- older children: delayed onset puberty
Definitive diagnosis of CF:
Definitive diagnosis is via a sweat test
Management of CF:
Cystic fibrosis is a chronic disease which requires multidisciplinary team management.
1.. Daily chest physiotherapy techniques are necessary to help clear mucus and prevent pneumonias.
2. Medical management of cystic fibrosis includes prophylactic antibiotics, bronchodilators, and medicines to thin secretions (e.g. dornase alfa).
3.Pancreatic enzyme replacement (creon) and fat-soluble vitamin supplementation (ADEK) are also useful.
4. Patients should also have influenza and pneumococcal vaccines
5. A last-resort for patients with end-stage pulmonary disease in cystic fibrosis may be a bilateral lung transplant.
Triad for diagnosis of CF:
- Typical pulmonary and/or gastrointestinal tract manifestations
- A family history
- A positive result on ‘sweat-test’ (based on Cl-ion concentration)
what does pilocarpine-iontophoresis sweat-test involve:
Involves pharmacological stimulation of sweating with pilocarpine; the amount of sweat is measured and its Cl concentration is determined. In patients with a suggestive clinical picture or a positive family history, a Cl concentration > 60 mmol/L confirms the diagnosis. In infants, a Cl concentration > 30 mmol/L is highly suggestive of CF. A minimum sweat-weight of 100 micrograms is also required.
respiratory pathogens involvement in CF:
Early in the course, Staphylococcus aureus is the pathogen most often isolated from the respiratory tract, but as the disease progresses, Pseudomonas aeruginosa is most frequently isolated. A mucoid variant of Pseudomonas is uniquely associated with CF.
Colonization with Burkholderia cepacia occurs in up to 7% of adult patients and may be associated with rapid pulmonary deterioration. I
n spite of the large number of organisms present in the airways and sputum, CF patients rarely become septic and blood cultures are not helpful. It is an airway colonization process and not a pneumonic one.
Chest Xray findings in CF:
- hyperinflation
- bronchiectasis
- lobar atelectasis
- large hila
Chest radiographs may initially be normal, however over time they typically show bronchial wall thickening and bronchiectasis.
Progressive air-trapping with bronchiectasis may be initially apparent in the upper lobes but may progress to all zones.
With advancing pulmonary disease there may be pulmonary nodules resulting from abscesses and atelectasis and marked hyperinflation with flattened domes of the diaphragm.
Pulmonary artery dilatation and right ventricular hypertrophy associated with cor-pulmonale is usually masked by the hyperinflation.
life expectancy of a newly diagnosed CF patient:
50-55yrs
Preventive stragies with regard to infection, vigorous regular chest physiotherapy, and periodic intensive antibiotic therapy have helped the survival and improved quality of life.
The use of nebulized rhDNase (Pulmozyme) can decrease the viscosity of CF mucus by aiding removal of excessive DNA from inflammatory cells destroyed in airways.
what conditions are associated with the Ashkenazi Jewish population?
Tay Sachs disease within the Ashkenazi Jewish population is often used as an example but in fact Gaucher’s Disease is more prevalent.
Tay-Sachs disease is part of a group of genetic disorders called the GM2 gangliosidoses. Affected children appear to develop without a problem until about 6 months of age and then begin to show neurological symptoms, including: Slowing of development. Progressive loss of mental ability
Gaucher’s disease: a lysosomal storage disorder.When you have Gaucher disease, you are missing an enzyme that breaks down fatty substances called lipids. Lipids start to build up in certain organs such as your spleen and liver.
Pierre Robin sequence triad & presentation:
Triad of:
1. micrognathia (small jaw)
2. glossoptosis: Posterior displacement of the tongue into the pharynx
3. airway obstruction
Karyotype of Down’s syndrome:
47,XX,+21 or 47,XY,+21
commonest cause of down’s syndrome:
approximately 95% of cases result from chromosomal non-disjunction of chromosome 21
karyotypes of Klinefelter syndrome:
47,XXY, but chromosome mosaics with 46,XY/47,XXY and complements with multiple X chromosomes like 48,XXXY are known
commonest karyotype of Turner’s syndrome;
45XO
what is faecal elastase used to assess?
The determination of faecal elastase 1 concentration is a simple means of assessing exocrine pancreatic function in children with cystic fibrosis. It is a rapid and reliable option to qualitatively evaluate pancreatic function in a diagnosed case of cystic fibrosis.
when is the heel prick test usually performed?
fifth day after birth
what genetic conditions does heel prick test identify:
It helps in identifying any of the nine rare conditions: cystic fibrosis; congenital hypothyroidism; phenylketonuria; classical galactosaemia; glutaric aciduria type 1; medium-chain acyl-CoA dehydrogenase deficiency; homocystinuria; maple syrup urine disease; and adenosine deaminase deficiency severe combined immunodeficiency.
