Paediatrics - Genetics? Flashcards
What causes Down’s syndrome?
Dysmorphic features? - 3 key ones
Complications?
Routine follow up investigaitons in down’s syndrome?
Down’s Syndrome is caused by three copies of chromosome 21. It is also called trisomy 21.
It gives characteristic dysmorphic features and is associated with a number of associated conditions.
Dysmorphic Features
Hypotonia (reduced muscle tone)
Brachycephaly (small head with a flat back - brachy = short)
Short neck
Short stature
Flattened face and nose
Prominent epicanthic folds (medial eyelid)
Upward sloping palpebral fissures (slanted eyes mate)
Single palmar crease
Complications:
Learning disability
Recurrent otitis media
Deafness. Eustachian tube abnormalities lead to glue ear and conductive hearing loss.
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
Management involves supportive care from the multidisciplinary team to help them meet their needs.
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
average life expectancy is 60 years
Antenatal Screening and testing for down’s syndrome?
Screening
The combined test is performed between 11 and 14 weeks gestation. It combines results from ultrasound and maternal blood tests:
- US - nuchal translucency above 6mm
- Blood tests - Beta-HCG (high result) and PAPPA (pregnancy-associated plasma protein-A) - (low result)
Testing:
- when the risk score from screening is higher than 1 in 150 chance of down’s syndrome
- Chorionic villus sampling before 15 weeks
- amnioscentisis - later in pregnancy (enough amniotic fluid to safely sample)
A 14 year old boy presents with his mum who is concerned about his development. On examination he is tall with wide hips, has gynaecomastica and small testes.
Likely diagnosis?
Pathophysiology?
Management?
Klinefelter syndrome occurs when a male has one (or more) additional X chromosome, making them 47 XXY.
Features
Usually patients with Kleinfelter syndrome appear as normal males until puberty. At puberty can develop features suggestive of the condition:
Taller height
Wider hips
Gynaecomastia
Weaker muscles
Small testicles
Reduced libido
Shyness
Infertility
Subtle learning difficulties (particularly affecting speech and language)
Ix - Karyotyping from a blood sample
Management:
There is no way to treat the underlying genetic cause of Klinefelter syndrome. Treatment aims to help with the features of the condition:
Testosterone injections improve many of the symptoms
Advanced IVF techniques have the potential to allow fertility
Breast reduction surgery for cosmetic purposes
MDT input for physio, educational support
Turners vs Kleinfelter’s syndrome
Turners - female with a single X - 45 XO
Kleinfelter’s - male with an extra X - 47 XXY
I think you’ve always known turners was female because of sheila turner.
A 13 year old girl presents to the GP with her mum who is concerned about her development. On examination you she is short in stature, has a webbed neck and a broad chest with widely spaced nipples.
Likely diagnosis?
Associated conditions?
Management?
Turner syndrome occurs when a female has a single X chromosome, making them 45 XO. The O referrs to an empty space where the other X chromosome should be. Life expectancy is close to normal.
Features
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 - CAME UP
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.
TOM TIP: The three classic features to remember and look out for in exams are short stature, webbed neck and widely spaced nipples.
Associated Conditions
Recurrent otitis media
Recurrent urinary tract infections
Coarctation of the aorta
Hypothyroidism
Hypertension
Obesity
Diabetes
Osteoporosis
Various specific learning disabilities
Ix: karyotyping
Management:
- no cure
- Growth hormone therapy can be used to prevent short stature
- Oestrogen and progesterone replacement can help establish female secondary sex characteristics, regulate the menstrual cycle and prevent osteoporosis
- Fertility treatment can increase the chances of becoming pregnant
treatment of associated conditions - hypothyroidism, hypertension
Inheritence pattern for Noonan syndrome
List some key features? 2 key
Associated conditions? 3key
There are a number of different genes that cause Noonan syndrome. The majority for cases are inherited in an autosomal dominant way.
Features
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
Basically - dysmorphic facial features
ME - THIS IS VERY VERY SIMILAR TO TURNER’S SYNDROME. BUT THE HYPERTELORISM IS UNIQUE HERE. ALSO CAN AFFECT MALES OR FEMALES
Associated Conditions - just try and remeber a few
Congenital heart disease, particularly pulmonary valve stenosis, hypertrophic cardiomyopathy and ASD
Cryptorchidism (undescended testes) can lead to infertility. Fertility is normal in women.
Learning disability
Bleeding disorders
Lymphoedema
Increased risk of leukaemia and neuroblastoma
MDT management. Congenital heart disease- corrective heart surgery.
This one you do need to know about…
Gene mutation that causes Fragile X-syndrome?
Inheritence pattern?
Features?
I think its the most common inherited cause of laerning disability
Fragile X syndrome is caused by a mutation in the FMR1 (fragile X mental retardation 1) gene on the X chromosome. The FMR1 gene codes for the fragile X mental retardation protein, which plays a role in cognitive development in the brain.
It is X-linked - HENCE THE NAME!, but it is unclear whether it is dominant or recessive. Males are always affected, but females can vary in how much they are affected. This is because females have a spare normal copy of the FMR1 gene on their other X chromosome. When the mother is phenotypically normal, the affected child may have inherited the X chromosome from their mother, or it may result from a de novo (random) mutation.
Fragile X syndrome usually presents with a delay in speech and language development. Other features are:
Intellectual disability
Long, narrow face
Large ears
Large testicles after puberty
Hypermobile joints (particularly in the hands)
Attention deficit hyperactivity disorder (ADHD)
Autism
Seizures
Management - supportive for symtoms, learning disability, ADHD autism and seizsures.
High Yield on Prada Willi:
What is Prader-Willi Syndrome?
2 key features
Key treatment?
Lower yield - other features
Prader-Willi Syndrome is a genetic condition caused by the loss of functional genes on the proximal arm of the chromosome 15 inherited from the father.
As infants there is poor muscle tone but as they grow they develop constant, insatiable hunger that leads to obesity.
Ix- genetic testing on infants with hypotonia and difficulty feeding/hypogonadism
Treatment - Growth hormone aimed at improving muscle development and body composition.
Dieticians play a very important role and strategies around lockign away food.
Other Features
Constant insatiable hunger that leads to obesity
Poor muscle tone as an infant (hypotonia)
Mild-moderate learning disability
Hypogonadism
Fairer, soft skin that is prone to bruising
Mental health problems, particularly anxiety
Dysmorphic features
Narrow forehead
Almond shaped eyes
Strabismus
Thin upper lip
Downturned mouth
gene affected in angelman syndrome?
3 Unique features to remeber
Loss of function of the UBE3A gene on chromosme 15 inherited from mother (Prada villi is also 15 but whole section of paternal chromosome). Can be a deletion, a point mutation or where both copies of 15 are contributed from the father with no maternal copy
The novel features to remember and link with Angelman syndrome so you can spot it in your exams is the unusual fascination with water, happy demeanour and widely spaced teeth.
Angelman - like fish, obsessed with water.
Other features:
- learning disiability
- delay in pseech development
- ataxia (balance and co-ordination issues)
- microcephaly
- hand flapping…
Like many genetic syndromes there is no cure and management is supportive with an MDT approach.
Genetic Cause of William Syndrome?
Distinctive features 3 and 2 key associations?
Management
Random deletion of genes in a region on chromosome 7 occouring at the time of conception, resulting on inheritence of a single copy of these genes.
TOM TIP: The distinctive features to remember with William syndrome are the very sociable personality, the starburst eyes (star-like pattern on the iris) and the wide mouth with a big smile. It is worth remembering the association with supravalvular aortic stenosis (narrowing just above the aortic valve) and hypercalcaemia, as these are unique features that are easy to test in exams.
Other features:
- broad forehead
- flatterned nasal bridge
- mild learning diability
Management
- MDT for indivual problems
- echocardiogram and blood pressure monitoring to assess for aortic stenosis and hypertension
- Low calcium diet, avoid vitmain D and calcium supplements.
What are edwards and patau syndrome
Trisomies (extra chromosome) just like in Down’s dynrome.
Patua - trisomy 13
Edwards trisomy - 18 E-ighteen mnemonic
Both edwards and pataus cause learning difficulty, structural abnormalities and dysmorphic features. Both also cause Covex shaped “rocker bottom feet” which is unique. Neither are compatible with longterm survival.
Down’s - trisomy 21. The most common
Duchenne’s muscular Dystrophy:
- what is muscular dystrophy
- clinical sign
- inheritence pattern?
- presentation
- management
Muscular dystrophy is an umbrella term for genetic conditions that cause gradual weakening and wasting of muscles. The main muscular dystrophy to know about for the purpose of exams is Duchennes muscular dystrophy
Gower’s sign is a sign of proximal muscle (around the pelvis) weakness where children walk their hands up their legs in order to stand up.
X-linked recessive - only boys!
It is caused by a defective gene for dystrophin on the X-chromosome. Dystrophin is a protein that helps hold muscles together at the cellular level. Given that boys have a single X-chromosome and girls have two, girls have a spare copy of the dystrophin gene. Female carriers of the condition do not usually notice any symptoms. This makes Duchennes muscular dystrophy an X-linked recessive condition. If a mother is a carrier (meaning she has one faulty gene) and she has a child, that child will have a 50% change of being a carrier if they female and 50% change of having the condition if they are male.
Boys with Duchennes present around 3 – 5 years with weakness in the muscles around their pelvis. The weakness tends to be progressive and eventually all muscles will be affected. They are usually wheelchair bound by the time they become a teenager. They have a life expectance of around 25 – 35 years with good management of the cardiac and respiratory complications (respiratory and cardiac muscle also involved).
Rx:
- Oral steroids have been shown to slow the progression of muscle weakness by as much as two years.
- Creatine supplementation can give a slight improvement in muscle strength.
- physiotherapy
- management of cardiac or respiratroy complications, including regular ECG and Echo.
Note - Becker’s muscular dystrophy is a less severe form of muscular dystrophy with mroe gradual progression caused by a less severe mutation in the dystriphin gene.
