Multi-system Disease

Question 1

Many multi-system disorders have a genetic aetiology. Why multi-system involvement?

Answer 1

• several genes with diverse functions are involved (chromosomal): extra copies of some or many genes (e.g. trisomy, duplications), or only single copies of some or many genes (e.g. monosomy, deletions, microdeletions (contiguous gene syndromes)).
• single gene widely expressed in different tissues
• single gene tissue-specific expression but tissue integral part of many different systems

Question 2

What are some common problems when investigating multi-system disease?

Answer 2

• variable expression within as well as between families - sometimes difficult to predict phenotype from genotype.
• present to a large variety of different specialists
• family history easily missed - often need to ask quite a range of questions to detect a positive FH.

On the plus side:
- considerable scope for screening and preventive interventions

Question 3

Neurofibromatosis Type 1 (NF1) characteristics and NIH diagnostic criteria.

Answer 3

• autosomal dominant
• prevalence 1/2500-3500

NIH diagnostic criteria - need 2 + for diagnosis:
- cafe au lait spots - 6 or more
- neurofibromas - 2 or more
- axillary freckling
- Lish nodules (specks in iris)
- optic glioma
- thinning of long bone cortex
- family history

Question 4

outline the diagnosis and management of NF1

Answer 4

• clinical diagnosis using diagnostic criteria

Management:
- annual review of affected individuals and at risk children until diagnosis can be excluded (5 years)
- BP monitoring and treatment
- check spine for scoliosis
- check tibia for unusual angulation
- check visual acuity and visual fields
- educational assessment
- ask patient to report an unusual symptoms

Question 5

Genetics of NF1

Answer 5

• autosomal dominant
• variable expression: inter-familial and intra-familial
• gene identified - 17q, a tumour suppressor gene
• mutations different in different families: test cost around £400 so used sparingly
• 50% due to new mutations, usually paternal in origin

Question 6

NF1 and NF2 are completely different disorders. Do not confuse them!
What are the main clinical features and genetics of NF2?

Answer 6

main clinical features:
- acoustic neuromas, usually bilateral
- CNS and spinal tumours
- a few CAL spots

NF2 gene is on chromosome 22.

Question 7

what are the clinical features of tuberous sclerosis complex (TSC)?

Answer 7

Classic Triad:
- epilepsy
- learning difficulty
- skin lesions

hamartomas in different organs e.g. eyes, brain, heart, kidneys, skin

Question 8

describe the genetics of tuberous sclerosis complex (TSC)

Answer 8

• autosomal dominant, 60% due to new mutations
• variable expression - severity varies between family members
• almost full penetrance - gene carriers will have some signs even if only on scans
• 2 genes on different chromosomes both cause TSC with identical phenotypes: TSC1 and TSC2

Question 9

TSC investigations

Answer 9

• clinical exam: skin signs, including Woods lamps, nails, retinal exam
• cranial MR scan
• renal US
• echocardiogram

Question 10

Features of Myotonic Dystrophy

genetic and clinical

Answer 10

• autosomal dominant
• CTG repeat, exhibits anticipation with increasing severity in each generation

Clinical Features:
- bilateral late-onset cataract
- muscle weakness, stiffness & myotonia
- low motivations, bowel problems, diabetes mellitus
- heart block
- death post-anaesthetic a risk if not monitored
- congenital myotonic dystrophy - death/severe muscle disorder and learning difficulty