Paediatrics Genetics Flashcards
Where and on what is the genetic code located?
In the nucleus of every cell within a long string of nucleotides on a molecule called deoxyribonucleic acid (DNA)
How many chromosomes do we have and where are they?
23 chromosome pairs or 46 chromosomes in total
What are the sex chromosomes?
X chromosome and Y chromosome (males have X and Y and females have two X chromosomes)
What are the ‘other chromosomes’ called?
Autosomes (non-sex chromosomes)
What is the genotype and phenotype respectively?
What is the process of creating a gamete (egg or sperm) called?
Meiosis
How do the genes for Huntington’s Chorea and Cystic Fibrosis differ?
HC = dominant
CF = recessive
What are the possible chromosome disorders?
Deletion
Duplication
Mosaicism
Translocation
Trisomy
What is a deletion disorder?
Portion of a chromosome is missing (very rare)
What is an example of a deletion disorder?
Cri du chat caused by a missing portion of chromosome 5
Patients have learning, developmental and speech and language difficulties and characteristic “cat like cry”
Give an example of a duplication disorder?
Charcot-Marie-Tooth which can be caused by duplication of short arm of chromosome 17 - patients have sensory and motor neuropathy with characteristic pes cavus (high arching foot)
What are the types of translocation disorders?
One portion of chromosome is directly swapped with another portion
Reciprocal translocation = balanced
Nonreciprocal translocation = unbalanced
What can translocation disorders cause?
Predisposes to other conditions e.g. cancer or infertility
E.g. “philadelphia chromosome” translocation in acute myeloid lukaemia (reciprocal translocation between chromosomes 9 and 22)
What are Robertsonian translocations?
Occur in acrocentric chromosomes (13, 14, 15, 21, 22) with longer arm with most of the genetic material and short arm with little genetic information on it
What are the 3 trisomys?
Trisomy 13 = Patau syndrome (varies in severity) - learning disability, polydactylyl, microcephaly, cleft lip
Trisomy 18 = Edwards syndrome (varies in severity) - LD, micrognathia, overlapping of fingers, rocker bottom feet
Trisomy 21 = Down’s syndrome (most common)
What is mosaicism?
Scenario where the chromosomal abnormality happens after conception in a portion of cells in body and not in others - each is unique and effects are unpredictable
What are mitochondria?
What is mitochondrial inheritance?
At time of conception the sperm carrying the fathers genetic material enters the egg and the DNA in the nucleus of both cells combine.
All the mitochondria in this comes from mother at mitochondria in sperm is in tail which doesn’t enter the egg
Called maternal inheritance
What is diagnosis testing?
Testing a fetus or a person for a suspected genetic condition
Give an example of diagnostic testing?
Test fetus for a genetic condition via amniocentesis e.g. Down’s syndrome
What is predictive testing give an example?
Testing a person for a gene mutation e.g. BRAC1 breast cancer gene or gene for Huntington’s chorea
What is carrier testing, give an example?
Testing parent / potential parent for specific autosomal recessive condition e.g. cystic fibrosis gene
What are some other specific tests?
Genealogical testing
Forensic testing
Paternity testing
What are the ethical issues surrounding genetic testing?
Get consent
Give genetic counselling before and discuss implications
What is karyotyping?
Looking at number of chromosome - size and basic structure - helpful in diagnosing Down’s syndrome (trisomy 21) and Turner syndrome (45XO)
What is microassay testing?
When is microassay testing used?
Screening for chromosomal abnormalities and common genetic conditions
Looking for mutations in cancer cells and for research aimed at matching genes with phenotypes
What is specific gene testing?
What is DNA sequencing?
For research only - split the two strands of DNA and watch as individual nucleotides are added to a single strand of DNA - ultimately revealing the exact sequence
What are the dysmorphic features of Down’s syndrome?
Hypotonia (reduced muscle tone)
Brachycephaly (small head with a flat back)
Short neck
Short stature
Flattened face and nose
Prominent epicanthic folds
Upward sloping palpable fissures
Single palmar crease
What are the complications of Down’s syndrome?
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
What is the combined test?
Between 11-14 weeks
Maternal bloods (b-HCG and PAPPA - high and low indicate greater risk)
US (Nuchal thickness > 6mm indicates greater risk)
What is the triple test?
Between 14-20 weeks
Maternal blood tests only:
- b-HCG (higher)
- AFP (lower)
- Serum oestriol (lower)
What is the quadruple test?
Performed between 14 and 20 weeks - identical to triple by includes maternal blood test for inhibin-A (if higher then indicates a greater risk)
What if the risk score for Down’s syndrome is greater than 1 in 150?
Offer amniocentesis or chorionic villus sampling - take a sample of fetal cells for karyotyping
How is chorionic villus sampling (CVS) performed?
Ultrasound guided biopsy of the placental tissue (done before 15 weeks)
How is amniocentesis performed?
Ultrasound guided aspiration of some amniotic fluid using a needle and syringe - done later in pregnancy when there is enough amniotic fluid to make it safer to take a sample
What is non-invasive prenatal testing (NIPT)
Maternal blood testing for fragments of fetal DNA - alternative to CVS/amniocentesis
What is the management of Down’s syndrome?
By MDT:
- OT
- SALT
- Physio
- Dietician
- Paediatricians
- Cardiologists
- ENT
- Charities e.g. Down’s syndrome association
What are the follow up investigations for Down’s syndrome?
- Regular thyroid checks (2 yearly)
- Echocardiogram to diagnose cardiac defects
- Regular audiometry for hearing impairment
- Regular eye checks
What is the life expectancy for Down’s syndrome?
60 years
What is Klinefelters syndrome?
Male has an additional X chromosome = 47 XXY (may have more Xs)
What are the features of Kleinfelter syndrome?
Appear as normal males until puberty, then:
Taller height
Wider hips
Gynaecomastia
Weaker muscles
Small testicles
Reduced libido
Shyness
Infertility
Subtle learning difficulties (particularly affecting speech and language)
What is the management for Kleinfelter syndrome?
No way to treat underlying genetic cause, treatment for features:
- Testosterone injections improve many of the symptoms
- Advanced IVF techniques have potential to allow fertility
- Breast reduction surgery for cosmetic purposes
- Speech and language therapy
- OT for help with everyday tasks
- Physio to strengthen muscles and joints
- Educational support required for dyslexia and other learning difficulties
What is the life expectancy with Kleinfelters?
Close to normal
What is Turner’s syndrome?
Female has a single X chromosome making them 45 XO (life expectancy is close to normal)
What are the features of Turner’s 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
What conditions are associated with Turner’s syndrome?
Recurrent otitis media
Recurrent urinary tract infections
Coarctation of the aorta
Hypothyroidism
Hypertension
Obesity
Diabetes
Osteoporosis
Various specific learning disabilities
What is the management of Turner’s syndrome?
Help with symptoms of condition
Growth hormone therapy to prevent short stature
Oestrogen and progesterone replacement to develop female secondary sex characteristics, regulate menstrual cycle and prevent osteoporosis
Fertility treatment to increase chances of becoming pregnant
What is Noonan syndrome?
Genetic condition - number of different genes which cause it
Majority of cases are inherited in an autosomal dominant way
What are the features of Noonan syndrome?
Webbed neck
Pectus excavatum
Short stature
Pulmonary stenosis
What conditions are associated with Noonan syndrome?
CVD (pulmonary valve stenosis, ASD)
Cryptorchidism (undescended testes)
LD
Lymphoedema
Increased risk of leukaemia and neuroblastoma
What is the treatment for Noonan syndrome?
Supportive with multidisciplinary team - main complication is congenital heart disease - often requiring corrective heart surgery
What is Marfan syndrome?
Autosomal dominant condition affecting the gene responsible for creating firbillin (an important component of connective tissue) meaning that people with Marfan syndrome have features resulting from abnormal connective tissue
What are the features of Marfan syndrome?
Tall stature
Long neck
Long limbs
Long fingers (arachnodactyly)
High arch palate
Hypermobility
Pectus carinatum or pectus excavatum
Downward sloping palpable fissures
What are the two tests for arachnodactyly?
Cross their thumb across their palm (if tip goes over then arach)
Wrap finger and thumb around other wrist (if overlap then arach)
What conditions are associated with Marfans?
Lens dislocation
Joint dislocation
Scoliosis of the spine
Pneumothorax
GORD
Aortic aneurym
What is the management of Marfan’s?
Greatest risk = cardiac complications (valve prolapse and aortic aneurysms) - surgical correction
Manage risk = avoid intense exercise, caffeine, BBs, A2RB
Pregnancy = risk of aortic aneurysm
Physio
Yearly echo and ophthalmology
What monitoring do patients with Marfan’s require?
Yearly echocardiograms and review by an ophthalmologist
What is fragile X syndrome caused by?
Mutation in FMR1 (fragile X mental retardation 1 gene) - plays a role in cognitive development of the brain
What is the pattern of inheritance of fragile X syndrome?
X-linked unclear if dominant or recessive - males are always affected but females affected to a varying level
What are the features of fragile X syndrome?
Presents with a delay in speech and language development, along with:
- Learning difficulties
Macrocephaly
Long face
Large ears
Macro-orchidism
What is the management of fragile X syndrome?
Supportive, multi-disciplinary team to support:
- Learning disability
- Autism
- ADHD
- Seizures
Life expectancy is similar to general population
What is Prada-Willi syndrome?
Loss of functional genes on the proximal arm of the chromosome 15 inherited from the father
What are the features of Prada-Willi syndrome?
Hypotonia
Hypogonadism
Obesity
What is the treatment of Prada-Willi syndrome?
No cure - carefully limit access to food (locking food in cupboards, putting lock on the fridge, controlling access to rubbish bins)
Growth hormone - improves muscle development and body composition
Who is involved in the management of Prada-Willi syndrome?
- Dieticians play in important role
- Educational support
- Social workers
- Psychologists
- Physiotherapists
- OTs
What is Angelman syndrome?
Loss of function of UBE3A gene on chromosome 15
What are the features of Angelman syndrome?
Delayed development and learning disability
Severe delay or absence of speech development
Ataxia
Fascination with water
Happy demeanour
Inappropriate laughter
Hand flapping
Abnormal sleep patterns
Epilepsy
Attention-deficit hyperactivity disorder
Dysmorphic features
Microcephaly
Fair skin, light hair and blue eyes
Wide mouth with widely spaced teeth
Who is involved in the management of Angelman syndrome?
Parental education
Social services and support
Educational support
Physiotherapy
Occupational therapy
Psychology
CAMHS
Anti-epileptic medication where required
What is William syndrome caused by?
Deletion of genetic material on one copy of chromosome 7
Usually the result of a random deletion around conception
What are the features of William syndrome?
Short stature
Learning difficulties
Friendly, extrovert personality
Transient neonatal hypercalcaemia
Supravalvular aortic stenosis
What conditions are associated with William syndrome?
Supravalvular aortic stenosis
Hypercalcaemia
ADHD
HTN
What is the management of William syndrome?
Echos and bp monitors to assess for aortic stenosis and hypertension
Low calcium diet required to control hypercalcaemia Avoid calcium and vit D supplements
