Genetics - Multi-system Disease Flashcards
(27 cards)
Multi-system disorders:
- Many multi-system disorders have a ________ aetiology
- Germ-line genetic variations present in every ____
genetic
cell
What are the Modes of inheritance in multi-system disorders?
All possible modes of inheritance - new mutations or inherited
- Chromosomal
- Single gene disorders
- Multifactorial
what are chromosomal modes of inheritance?
numerical eg trisomy 21
structural eg translocations, deletions and microdeletions
what are the different ways single gene disorders can be a mode of inheritance?
autosomal dominant eg TS, NF1, myotonic dystrophy
autosomal recessive eg Cystic fibrosis
X- linked eg Duchenne muscular dystrophy
what multifactorial ways can be a mode of inheritance?
polygenic
environmental factors:
- haemochromatosis (nherited condition where iron levels in the body slowly build up over many years)
- diabetes
Why multi-system involvement?
•Several genes with diverse functions are involved (chromosomal):
- extra copies of some or many genes - trisomy, duplications
- only single copies of some or many genes - 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
what are some common problems in multi-system disease?
- 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 wide range of questions to detect a positive FH
On the plus side - Considerable scope for screening and preventive interventions
Neurofibromatosis Type 1 (NF1) (Von Recklinghausen disease) - what is the epidemiology?
- Autosomal dominant
- Prevalence 1/2500 - 3500
how is a diagnosis of NF1 made?
NIH diagnostic criteria - need 2+ for diagnosis:
- café au lait spots - 6 or more
- neurofibromas - 2 or more
- axillary freckling
- Lisch nodules (specks in iris)
- optic glioma
- thinning of long bone cortex
- family history
what are further features of NF1?
- Macrocephaly (large head)
- Short stature
- Dysmorphic features- “Noonan look”
- Learning difficulties - Most have some, often subtle, 10% special schooling, 3% moderate MH
- Epilepsy
- Scoliosis
- Pseudoarthrosis of the tibia
- Raised BP - due to renal artery stenosis or phaechromocytoma
- Neoplasia - CNS (optic gliomas), endocrine
what is the Diagnosis of NF1?
•Clinical diagnosis using diagnostic criteria
what is the management of NF1?
- annual review of affected individuals and at risk children until diagnosis can be excluded (5 years)
- BP
- spine for scoliosis
- tibia for unusual angulation
- visual acuity and visual fields
- educational assessment
- ask patient to report any unusual symptoms
what is the genetics of NF1?
- Autosomal dominant
- Variable expression - inter-familial and intra-familial
- Gene identified - 17q - tumour suppressor gene
- Mutations different in different families - Test cost around £400 so used sparingly
- 50% due to new mutations - usually paternal in origin
are NF1 and NF2 the same?
NF1 and NF2 are completely separate disorders!
Do not confuse NF1 and NF2
what are the main features of NF2?
- acoustic neuromas »usually bilateral
- CNS and spinal tumours
- a few CAL spots
•NF2 gene is on Chromosome 22
what is Tuberous Sclerosis (TS)?
Tuberous sclerosis, also known as tuberous sclerosis complex, is a rare genetic condition that causes mainly non-cancerous (benign) tumours to develop in different parts of the body
- Incidence 1 in 7000 newborns
- Autosomal dominant
- Hamartomas (noncancerous tumour) in different organs
what is the classic traid of TS?
Epilepsy
Learning difficulty
Skin lesions
what is the Genetics of TS?
- Autosomal dominant - 60% due to new mutations
- Variable expression - severity varies between family members
- Almost full penetrance (if fully investigated) - gene carriers will have some signs even if only on scans
- 2 genes on different chromosomes both cause TS with identical phenotypes:
- TSC1
- TSC2
what are the clinical features of TS?
- Multi-system
- Variable expression - asymptomatic to severe mental and occasionally physical handicap
- Learning difficulty 40% - Autistic features common
- Seizures 65%:
- infantile spasms
- myoclonic seizures
what are osme other features of TS?
•Skin lesions:
- depigmented macules
- angiofibromas
- fibrous plaque forehead
- hagreen patches
- ungual fibromas
- Kidney - cysts and angiomyolipomata
- Phakomas in eye - benign unless on macula
- Rhabdomyomas in heart
pictures showing features of TS
more pictures showing TS features
what are the lcinical features of TS?
how is Screening of at-risk relatives done?
- Siblings and parents may be mildly affected
- Surveillance and genetic counselling
- Clinical examination
- skin signs, including Woods lamp, nails
- retinal examination
- Cranial MR scan
- Renal ultrasound
- Echocardiogram
