Genetics: Multi-system genetic disorders Flashcards
What are the modes of inheretance in multi-system disorders?
- new mutations or inherited
- Chromosomal
□ numerical e.g. trisomy 21
□ structural e.g. translocations, deletions and microdeletions - Single gene disorders
□ autosomal dominant e.g. TS, NF1, myotonic dystrophy
□ autosomal recessive e.g. Cystic fibrosis
□ X- linked e.g. Duchenne muscular dystrophy - Multifactorial
□ polygenic
□ environmental factors
® haemochromatosis
® Diabetes
Why is there 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 the 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
I sneurofibromatosis type 1 (Von Recklinghausen disease) aurosomal dominant or recesisve?
Autosomal dominant
What are the NIH diagnostic chriteria for neurofibromatosis type 1 (Von Recklinghausen disease)?
- 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 further features can someone with neurofibromatosis type 1 (Von Recklinghausen disease) develop?
- Macrocephaly
- 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
How is neurofibromatosis type 1 (Von Recklinghausen disease) diagnosed?
Clinical diagnosis using diagnostic criteria
What is the management of neurofibromatosis type 1 (Von Recklinghausen disease)?
- 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 are the genetics of neurofibromatosis type 1 (Von Recklinghausen disease)?
- 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 neurofibromatosis type2?
- The main features of NF2 are: □ acoustic neuromas □ usually bilateral □ CNS and spinal tumours □ a few CAL spots - NF2 gene is on Chromosome 22
What is the classic triad of tuberous sclerosis?
- Epilepsy
- Learning difficulty
- Skin lesions
What is the genetics of teberous sclerosis?
- 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 tuberous sclerosis?
- 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 other features can someone with tuberous sclerosis present with?
- 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
What screening takes place for at risk relatives of someone with tuberous sclerosis?
- 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
