Genetics of Multi System Disorders Flashcards
Features of multi system disorders
affect more than one system
many have a genetic aetiology
Germ line genetic variations present in every cell
Modes of inheritance in multi system disorders
New mutations or inherited
Chromosomal
- numerical e.g. trisomy 21
- structural e.g. translocations/deletions
Single gene disorders
- autosomal dominant
- autosomal recessive e.g. cystic fibrosis
- X linked e.g. duchenne muscular dystrophy
Multifactorial
- polygenic
- environmental factors (hemochromatosis, DM)
What is multi system involvement?
Several genes with diverse functions are involved (chromosomal)
- extra copies of some genes
- only single copies of some genes
Single gene widely expressed in different tissues
Single gene tissue specific expression but tissue integral part of many systems
Common problems in multi system disease
Variable expression within as well as between families
Present to a large variety of different specialists
FH easily missed
Genetics of neurofibromatosis type 1 (NF1)
Autosomal dominant
NIH diagnostic criteria for neurofibromatosis type 1 (need 2+)
Café au lait spots - 6 or more neurofibromas - 2 or more axillary frecking Lisch nodules (specks in iris) optic glioma thinning of long bone cortex FH
Presentation of neurofibromatosis type 1
Café au lait spots neurofibromas axillary freckling lisch nodules (specks in iris) optic glioma thinning of long bone cortex macrocephaly short stature dysmorphic features - Noonan look LDs Epilepsy Scoliosis Pseudoarthritis of the tibia Raised BP Neoplasia - CNS (optic gliomas, endocrine)
Treatment of neurofibromatosis type 1
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
Genetics of neurofibromatosis
Autosomal dominant Variable expression - inter-familial and intra-familial Gene identified - 17q - tumour suppressor gene Mutations different in different families 50% due to new mutations - usually paternal in origin
Features of neurofibromatosis (NF2)
Acoustic neuromas (usually bilateral)
CNS and spinal tumours
A few CAL spots
Where is the NF2 gene?
On chromosome 22
Classic triad of tuberous sclerosis (TS)
Epilepsy
Learning Difficulty
Skin Lesions
Genetics of Tuberous sclerosis (TS)
Autosomal dominant
Presentation of TS
variable expression - asymptomatic to severe mental and occasionally physical handicap Epilepsy LDs - autistic features common Skin lesions - depigmented macules - angiofibromas - fibrous plaque forehead Hamartomas in different organs seizures - infantile spasms - myoclonic seizures Kidney - cysts - angiomyolipomata Phakomas in eye - benign unless on macula
Screening for TS of at risk relatives
Genetic counselling Surveillance Clinical exam Cranial MR scan Renal USS Echocardiogram
