Genetics and syndromes 3

Question 1

What is tuberous sclerosis?

Answer 1

Dominant inheritance
up to 70% are new mutations in TSC1 & TSC2 genes, which code for the proteins hamartin and tuberin respectively- these are tumour suppressor genes
• Prevalence is 1 in 9000 live births- affects brain, skin, heart, kidney, eye & lung

Question 2

How is tuberous sclerosis diagnosed?

Answer 2

o Definite diagnosis- two major features or one major feature with ≥2 minor features
o Possible diagnosis- either one major feature or ≥2 minor features

Question 3

What are the major and minor features of tuberous sclerosis?

Answer 3

•	Major features:
o	Facial angiofibromas
o	Ungul fibroma
o	Hypomelanotic macules->3
o	Shagreen patch
o	Subependymal (subE) nodules
o	subE giant cell astrocytoma
o	Retinal nodular haematoma
o	Cardiac rhabdomyhomata
Minor features: 
o	Pits in dental enamel
o	Rectal polyps
o	Bone cysts
o	Cerebral white matter ‘migration tracts’
o	Gingival fibromas
o	Non-renal haematoma
o	Retinal achromic patch
o	Confetti skin lesions
o	Multiple renal cysts

Question 4

What are the features of NF1?

Answer 4

o Neurofibromata appear in the course of any peripheral nerve- including cranial nerves, they may look unsightly or cause neurological signs if they occur at a site where a peripheral nerve passes through a bony foramen
o Visual or auditory impairment may result if there is compression of the 2nd or 8th cranial nerves
o Megalencephaly with learning difficulties and epilepsy are sometimes seen

Question 5

What are the features of NF2?

Answer 5

Bilateral acoustic neuroma
deafness and sometimes a cerebellopontine angle syndrome with a facial (7th) nerve paresis and cerebellar ataxia
• There may be an overlap between the features of NF1 & NF2- both can be associated with endocrinological disorders the multiple endocrine neoplasia (MEN) syndromes

Question 6

What are the cutaneous features of tuberous sclerosis?

Answer 6

o Depigmented ‘ash-leaf’ shaped patches which fluoresce under UV light
o Roughened patches of skin usually over lumbar spine-shagreen patches
o Adenoma sebaceum in a butterfly distribution over the bridge of the nose & cheeks, which are unualt before the age of 3yrs- angiofibromata

Question 7

What are the neurological signs of tuberous sclerosis?

Answer 7

o Infantile spasms and developmental delay
o Epilepsy- often focal
o Intellectual impairment
• These children have severe learning difficulties and often have autistic features to their behaviour when older

Question 8

What are the long term health conditions associated with neurofibromatosis?

Answer 8

• Phaeochromocytoma
• Pulmonary hypertension
• Renal artery stenosis with HTN
• Gliomatous change- particular CNS lesions
• Skeletal dysplasia
• Cognitive impairment

Question 9

What are the long term conditions associated with tuberous sclerosis?

Answer 9

• Fibromata beneath the nails- subungual fibromata
• Dense white areas on the retina from local degeneration- ophthalmological haematomata
• Cardiac rhabdomyoamata- identified in the early weeks on echo, but usually resolve in infancy
• Polycystic kidneys
• Gliomatous change can occur in the brain lesions
• Symptomatic epilepsy
• Pulmonary lymphangiomatosis- only affects girls

Question 10

What is achondroplasia?

Answer 10

autosomal dominant condition- about 50% are new mutations

affects the FGFR3 gene on chromosome 4p16

Question 11

What are the clinical features of achondroplasia?

Answer 11

Become obvious in first year of life 
o	Short stature from marked shortening of the limbs
o	Large head
o	Frontal bossing
o	Depression of the nasal bridge
o	Short/broad hands- ‘trident’ hand
o	Marked lumbar lordosis develops
o	Hydrocephalus sometimes occurs

Question 12

What are the longer term problems associated with achondroplasia?

Answer 12

o Difficulty in arm functioning & locomotion
o Neurological problems due to spinal canal stenosis- ataxia, incontinence, pain, quadriparesis
o Early osteoarthritis
o May be obese
o Develop varus leg deformity
o Develop lordosis & kyphosis
o Develop new or more severe spinal stenosis
o Respiratory complications- apnoea

Question 13

What are the ENT abnormalities associated with achondroplasia?

Answer 13

Narrow passages 
	Otitis media
	Speech delay
	Deafness
	Jaw malocclusion
	URTI

Question 14

What is Phenylketonuria (PKU)?

Answer 14

• Occurs in 1 in 10,000-15,000 live births in the UK- due to deficiency of the enzyme phenylalanine hydroxlase (classical PKU) or in the synthesis/recycling of the biopterin cofactor for this enzyme
• It untreated, it usually presents with developmental delay at 6-12 months
there may be a musty odour due to the metabolite pheylacetic acid
• Many affected children are fair-haired and blue-eyed some develop eczema and seizures

Question 15

How is PKU diagnosed?

Answer 15

phenylalanine accumulates and is converted into phenylketones- which are detected in the urine
• Most children are detected through the national biochemical screening programme- heel prick test (Guthrie test)

Question 16

What is the management for PKU

Answer 16

Most babies appear healthy at birth and if treated in the first 3 weeks of life show no problems
o Restriction of dietary phenylalanine & high tyrosine- avoid meats, eggs, fish, cheese, beer, flour & aspartame (diet drinks)
o Blood plasma phenylalanine is monitored regularly
o Recommendation to maintain diet throughout life, particularly important during pregnancy as it is a teratogen
o Mental health assisted- high levels of depression, anxiety disorder and phobias are also common
o Sapropterin- a drug used in some children as it is an enzyme that encourages PAH to work, it is very expensive (£100,000 per year)

Question 17

How are PKU co-factor defects treated?

Answer 17

Much poorer prognosis than classical PKU- treated with diet low in phenylalanine and neurotransmitter precursors