Genetics and syndromes Flashcards
How might the extra chromosome arise in Down’s?
The extra chromosome 21 may result from:
- Meiotic nondisjunction (94%)
- Translocation (5%)
- Mosaicism (1%)
What is meiotic non-disjunction?
- Pair of chromosome 21s fails to separate → 1 gamete has 2 chromosome 21s and 1 has none
- Fertilisation of gamete with 2 chromosome 21s gives rise to zygote with trisomy 21
- Parental chromosomes do not need to be examined
–> Related to maternal age
1 in how many live births have Down’s?
1 in 650
Typical craniofacial features of Down’s?
- Round face and flat nasal bridge
- Upslanted palpebral fissures
- Epicanthic folds (fold of skin running across inner edge of palpebral fissure)
- Brushfield spots in iris (pigmented spots)
- Small mouth and protruding tongue
- Small ears
- Flat occiput and third fontanelle
Other abnormalities in Down’s?
- Short neck
- Single palmar creases
- Incurved fifth finger
- Wide ‘sandal’ gap between toes
- Hypotonia
- Congenital heart defects (40%)
- Duodenal atresia
- Hirschsprung disease
Long-term problems associated with Down’s?
- Delayed motor milestones
- Mod- severe learning difficulties
- Small stature
- Increased susceptibility to infections
- Hearing impairment from secretory otitis media
- Visual impairment from cataracts, squints, myopia
- Increased risk of leukaemia and solid tumours
- Risk of atlantoaxial instability
- Increased risk of hypothyroidism and coeliac disease
- Epilepsy
- Alzheimer’s disease
Genotype for Turners?
45, X
- In 50% –> 45 chromosomes, only 1 X
- Others have deletion of short arm of 1 X chromosome, an isochromosome that has 2 long arms but no short arm, or variety of other structural defects of 1 X chromosome
What 2 characteristics occur in almost all with Turner’s?
- Being shorter than average height
- Lack of development of ovaries → infertility
Other clinical features of Turners?
- Lymphoedema of hands and feet in neonates
- Spoon-shaped nails
- Short stature – a cardinal feature
- Neck webbing or thick neck
- Wide carrying angle
- Widely spaced nipples
- Congenital heart defects (esp coarctation)
- Delayed puberty
- Ovarian dysgenesis–> infertility (pos IVF with donated egg)
- Hypothyroidism
- Renal anomalies
- Pigmented moles
- Recurrent otitis media
- Normal intellectual function in most
Long-term problems of Turners?
- Heart murmur
- Underactive thyroid
- High BP
- Osteoporosis
- Scoliosis
- Diabetes
- Lymphoedema
- GI bleeding
- Kidney and urinary tract problems
Management of Turners?
- Regular health checks
- → Hearing, BP, TFTs, glucose levels and bone mineral density
- GH therapy for girls not growing normally
- GH started age 5 or 6 but can be started later and usually continues until 15 or 16
- GH can give many SEs - headaches, visual problems, nausea, vomiting, joint pain, insulin resistance and underactive thyroid
- Oestrogen and progesterone replacement therapy given to aid sexual development and maintain until 50y
- Treatment should be started around 12-15y to minimise effect on growth
- Fertility cannot be restored but IVF + ova donation is a viable alternative
3 main components of foetal alcohol syndrome?
- Facial abnormalities (esp in mid-facial area)
- IUGR and failure to catch up
- Mental problems of cognitive impairment, learning disabilities and impulsiveness
Mode of inheritance of Duchenne muscular dystrophy?
X linked recessive
- 1/3 have new mutations
Clinical features of DMD?
- Waddling gait +/or language delay
- Mount stairs 1 by 1 and run slowly compared peers
- Av age of diagnosis = 5.5y
- Gowers sign (need to turn prone to rise)
- Pseudohypertrophy of calves because of replacement of muscle fibres by fat and fibrous tissue
- Early school years, affected boys tend to be slower and clumsier than peers
- Progressive muscle atrophy and weakness → no longer ambulant by 10–14y
- Life expectancy = late 20s → resp failure or associated cardiomyopathy
- 1/3 have learning difficulties
- Scoliosis = common complication
Early signs of DMD?
- Difficulty climbing stairs
- Slower walking
- Fall more often than expected
- Gower’s sign
Ix for DMD? (3)
Serum creatinine phosphokinase (CPK) raised
FH
Muscle biopsy - diagnostic
Management of DMD?
Maintain mobility:
- Exercise to maintain muscle power and mobility
- Lengthening of Achilles tendon
- Contractures prevented by passive stretching and provision of night splints
- Ambulant children treated with corticosteroids → preserve mobility and prevent scoliosis
Scoliosis:
- Appropriate exercise
- Maintain good sitting posture
- Scoliosis managed with truncal brace, moulded seat and ultimately surgical insertion of metal spinal rod
Respiratory:
- Resp aids, esp overnight CPAP or NIPPV
Other:
- Children reviewed periodically at specialist regional centre
What is neurofibromatosis?
Genetic condition that causes nerve tissue to grow benign tumours
Diagnostic criteria for T1 neurofibromatosis?
2 or more of:
- ≥6 café au lait spots >5mm in size before puberty, >15mm after puberty
- > 1 neurofibroma - unsightly firm nodular overgrowth of any nerve
- Axillary freckles
- Optic gliomas - may cause visual impairment
- 1 Lisch nodule - a hamartoma of iris seen on slit-lamp examination
- Bony lesions from sphenoid dysplasia - can cause eye protrusion
- 1st degree relative with NF1
Diff b/w T1 and T2 neurofibromatosis?
T1 = peripheral nerves T2 = CNS
What is tuberous sclerosis?
Genetic condition that causes non-malignant tumours to grow in the brain and other vital organs
- Dominant inheritance yet 70% may be new mutations
Clinical features of tuberous sclerosis?
Typically presents <5y with skin changes and epilepsy
Cutaneous features:
- Depigmented ‘ash leaf’shaped patches which fluoresce under UV light (Wood’s light)
- Roughened patches of skin (shagreen patches) usually over lumbar spine
- Adenoma sebaceum (angiofibromata) in butterfly distribution over bridge of nose and cheeks - unusual <3y
Neurological features:
- Infantile spasms and developmental delay
- Epilepsy – often focal
- Intellectual impairment
- Severe learning difficulties and often have autistic features when older
Other features:
- Fibromata beneath nails (subungual fibromata)
- Dense white areas on retina (phakomata) from local degeneration
- Rhabdomyomata of heart - identifiable in early weeks on echocardiography → usually resolve in infancy
- Polycystic kidneys
