multisystem disease Flashcards
mode of inheritance in multi-system disorders
all possible modes of inheritance - new mutations or inherited
chromosomal
single gene disorders
multifactorial
mode of inheritance in multi-system disorders - chromosomal
numerical e.g. trisomy 21
structural e.g. translocations, deletions, micro-deletions
mode of inheritance in multi-system disorders - single gene disorders
autosomal dominant - TS, NF1, myotonic dystrophy
autosomal recessive - CF
- X linked - Duchenne muscular dystrophy
mode of inheritance in multi-system disorders - multifactorial
polygenic
environmental - haemochromatosis, diabetes
what causes multisystem involvement
several genes with diverse functions involved (chromosomal disorder)
- extra copies of some/many genes (trisomy, duplication)
- only single copies of some/many genes (monosomy, deletions, microdeletions) - known as contiguous gene syndromes
single gene widely expressed in different tissues
single gene tissue specific expression but tissue integral part of many different systems
common problems in multisystem disease
variable expression within and between families
- difficult to predict phenotype from genotype
present to a large variety of different specialists
FHx easily missed
- need to ask a wide range of Qs to detect +ve FHx
BUT considerable scope for screening and preventative interventions
alternative name for neurofibromatosis type 1
Von Recklinghausen disease
inheritance of NF1
prevalence
autosomal dominant
1/3500
NIH diagnostic criteria for NF1
need ≥2 for diagnosis
café au lait spots - 6 or more neurofibromas - 2 or more axillary freckling Lisch nodules (specks in iris) optic glioma (tumour of optic nerves, can lead to loss of sight) thinning of long bone cortex FHx of NF1
what are these
cafe au lait spots
note smooth edge (sporadic, incidental patches often have a much more wrinkly edge than those associated w/ NF1)
not always present at birth and can become more visible w/ age
what are these
cutaneous neurofibromas
what are these
Lisch nodules
brown/pale raised nodules present on the surface of the iris
best viewed with a slit lamp but can be seen by fundoscopy
often one of the earliest seen features
what are these
plexiform neurofibromas
can be disfiguring and are quite infiltrating lesions
generally slow growing
can transform and become malignant lesions
common in the eyelid region and around the orbit
further features of NF1
- macrocephaly
- short stature
- dysmorphic features - Noonan look
- learning difficulties - most have some, often subtle, 10% special schooling, 3% moderate learning disability
- epilepsy - lesions in the brain
- scoliosis
- tibial dysplasia
- raised BP (renal artery stenosis or phaeochromocytoma)
- neoplasia (malignant peripheral nerve sheath tumours, CNS tumours - optic gliomas, gliomas) - 5% risk
what is this
tibial dysplasia (pseudoarthrosis)
genetics of NF1
autosomal dominant
variable expression - interfamilial and intrafamilial
gene on 17q - tumour suppressor gene
wide range of mutations in different families (~405 recurrent)
- whole gene needs to be sequenced to test for it
- tests are expensive so used sparingly
50% due to new mutations
- usually paternal in origin
how is NF1 diagnosed
clinical diagnosis using diagnostic criteria
management of NF1
- annual review of affected individuals and at risk children until diagnosis can be excluded (5yrs)
- annual BP
- spine for scoliosis
- tibia for unusual angulation
- visual acuity and fields
- educational assessment
- ask pt to report any unusual symptoms
- Selumetinib can shrink plexiforms but side effects (MEK inhibitor)
NF2 features
gene affected
completely separate disorder to NF1
NF2 is much rarer
- acoustic neuromas - usually bilateral
- CNS and spinal tumours
- a few CAL spots
NF2 gene is on chromosome 22
NF2 features
gene affected
completely separate disorder to NF1
NF2 is much rarer
- acoustic neuromas - usually bilateral
- CNS and spinal tumours
- a few CAL spots
NF2 gene is on chromosome 22
tuberous sclerosis incidence
1/7000 newborns
classic triad in TS
epilepsy - young onset, difficult to treat
learning difficulty
skin lesions
also hamartomas in different organs
genetics of TS
autosomal dominant - 60% due to new mutations
variable expression - severity varies between family members
almost full penetrance (if fully investigated) - gene carries will have some signs even if only on scans
2 genes on different chromosomes both cause TS w/ identical phenotypes - TSC1, TSC2
clinical features of TS
multi system
variable expression - asymptomatic to severe mental and occasionally physical diasability
learning difficulty 40% - autistic features common
seizures 65% - infantile spasms, myoclonic seizures
skin lesions (depigmented macules, angiofibromas, fibrous plaque forehead, shagreen patches, ungual fibromas)
kidney - cysts and angiomyolipomata
phakomas in eye (benign unless on macula)
rhabdomyomas in heart
