Genetics - Multisystem disease Flashcards
What are the three main modes of inheritance in multi-system disorders?
New mutations or inherited.
- Chromosomal (new): eg numerical trisomy 21 or structural translocations, deletions and microdeletions
- Single gene disorders (inherited):
- autosomal dominant eg TS, NF1, myotonic dystrophy
- autosomal recessive eg Cystic fibrosis
- X- linked eg Duchenne muscular dystrophy
- Multifactorial:
- polygenic
- environmental factors: haematomachrosis, DM
Why is there multisystem involvement?
- Several genes with diverse functions are involved in the pathological process:
- 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 (like a collagen fibre - parts of many tissues, so genetic mutation in this will be present commonly)
What are some common problems that arrise in multisystem disease?
- Variable expression within (as well as between) families
- sometimes difficult to predict phenotype from genotype
- Hard to tell how severe the SSx will be from just the genotype
- Present to a large variety of different specialists
- Fam history is easily missed: often need to ask quite a wide range of questions to detect a positive FH
What is neurofibromatosis type 1 (NF1)?
- A multisystem genetic disorder that is characterized by cutaneous findings
- Causes tumours to grow along your nerves. The tumours are usually non-cancerous (benign) but may cause a range of symptoms.
What are the genetic characteristics of NF1?
- Autosomal dominant
- Prevalence 1/2500 - 3500
What is the diagnostic criteria for NF1?
- 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 (occurs in optic chiasm - loss of vision)
- thinning of long bone cortex
- family history
What are some further features of NF1?
- Macrocephaly (larger than normal head size)
- 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 management of NF1?
- offer annual review of affected individuals and at risk children until diagnosis can be excluded (5 years) or genetic test will confirm diagnosis
- BP
- spine for scoliosis
- tibia for unusual angulation
- visual acuity and visual fields
- educational assessment
- ask patient to report any unusual symptoms
Please explain the genetics of NF1 and the consequences of this.
- Autosomal dominant
- Variable expression
- inter-familial and intra-familial
- Gene identified - 17q
- tumour suppressor gene
- Mutations different in different families
- therefore no simple diagnostic test
- 50% due to new mutations
- usually paternal in origin
What is the difference between NF1 and NF2?
Do not confuse these - they are completely different.
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 scelorosis? [TS]
A rare multisystem genetic disease that causes benign tumors (hamartomas) to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin.
- Incidence: 1/7000 newborns
What is the classic triad of TS?
- Epilepsy
- Learning difficulty
- Skin lesions
What are the genetic features 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
What are the genes responsible for TS?
- 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% (very common and can be very severe)
- infantile spasms
- myoclonic seizures
