Genetics and syndromes

Question 1

How might the extra chromosome arise in Down’s?

Answer 1

The extra chromosome 21 may result from:

• Meiotic non­disjunction (94%)
• Translocation (5%)
• Mosaicism (1%)

Question 2

What is meiotic non-disjunction?

Answer 2

• 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

Question 3

1 in how many live births have Down’s?

Answer 3

1 in 650

Question 4

Typical craniofacial features of Down’s?

Answer 4

• 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 


Question 5

Other abnormalities in Down’s?

Answer 5

• Short neck
• Single palmar creases
• Incurved fifth finger
• Wide ‘sandal’ gap 
between toes
• Hypotonia
• Congenital heart defects (40%)
• Duodenal atresia
• Hirschsprung disease

Question 6

Long-term problems associated with Down’s?

Answer 6

• 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

Question 7

Genotype for Turners?

Answer 7

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

Question 8

What 2 characteristics occur in almost all with Turner’s?

Answer 8

• Being shorter than average height

- Lack of development of ovaries → infertility

Question 9

Other clinical features of Turners?

Answer 9

• 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

Question 10

Long-term problems of Turners?

Answer 10

• Heart murmur
• Underactive thyroid
• High BP
• Osteoporosis
• Scoliosis
• Diabetes
• Lymphoedema
• GI bleeding
• Kidney and urinary tract problems

Question 11

Management of Turners?

Answer 11

• 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

Question 12

3 main components of foetal alcohol syndrome?

Answer 12

• Facial abnormalities (esp in mid-facial area)
• IUGR and failure to catch up
• Mental problems of cognitive impairment, learning disabilities and impulsiveness

Question 13

Mode of inheritance of Duchenne muscular dystrophy?

Answer 13

X linked recessive

- 1/3 have new mutations

Question 14

Clinical features of DMD?

Answer 14

• 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

Question 15

Early signs of DMD?

Answer 15

• Difficulty climbing stairs
• Slower walking
• Fall more often than expected
• Gower’s sign

Question 16

Ix for DMD? (3)

Answer 16

Serum creatinine phosphokinase (CPK) raised
FH
Muscle biopsy - diagnostic

Question 17

Management of DMD?

Answer 17

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

Question 18

What is neurofibromatosis?

Answer 18

Genetic condition that causes nerve tissue to grow benign tumours

Question 19

Diagnostic criteria for T1 neurofibromatosis?

Answer 19

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

Question 20

Diff b/w T1 and T2 neurofibromatosis?

Answer 20

T1 = peripheral nerves
T2 = CNS

Question 21

What is tuberous sclerosis?

Answer 21

Genetic condition that causes non-malignant tumours to grow in the brain and other vital organs
- Dominant inheritance yet 70% may be new mutations

Question 22

Clinical features of tuberous sclerosis?

Answer 22

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