Genetics - Multisystem Disease

Question 1

give examples chromosomal causes of multisystem disorders

Answer 1

• numerical eg trisomy 21

* structural eg translocations, deletions and microdeletions

Question 2

give examples of single gene disorders in multisystem disorders

Answer 2

• autosomal dominant eg TS, NF1, myotonic dystrophy
• autosomal recessive eg Cystic fibrosis
• X- linked eg Duchenne muscular dystrophy

Question 3

why is there multisystem involvement?

Answer 3

• 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

Question 4

common problems in multisystem disease

Answer 4

• 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

Question 5

neurofibromatosis type 1: inheritance

Answer 5

autosomal dominant

Question 6

neurofibromatosis type 1: diagnostic criteria

Answer 6

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

Question 7

neurofibromatosis type 1: other features

Answer 7

• 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

Question 8

neurofibromatosis type 1: management

Answer 8

• 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

Question 9

neurofibromatosis type 1: genetics

Answer 9

• 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

Question 10

main features of neurofibromatosis type 2

Answer 10

• acoustic neuromas
• usually bilateral
• CNS and spinal tumours
• a few CAL spots

Question 11

on what chromosome is the neurofibromatosis type 2 gene found?

Answer 11

22

Question 12

tuberous sclerosis: classic triad

Answer 12

epilepsy
learning difficulty
skin lesions

Question 13

tuberous sclerosis: inheritance

Answer 13

autosomal dominant

Question 14

tuberous sclerosis: genetics

Answer 14

• 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

Question 15

tuberous sclerosis: clinical features

Answer 15

• Multi-system
• Variable expression
• asymptomatic to severe mental and occasionally physical handicap
• Learning difficulty 40%
• Autistic features common
• Seizures 65%
• infantile spasms
• myoclonic seizures

Question 16

tuberous sclerosis: other features

Answer 16

• 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

Question 17

screening of at risk relatives in tuberous sclerosis

Answer 17

• 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

Question 18

myotonic dystrophy: inheritance

Answer 18

autosomal dominant

Question 19

myotonic dystrophy: genetics

Answer 19

CTG repeat

exhibits anticipation with increasing severity in each generation

Question 20

myotonic dystrophy: features

Answer 20

• Bilateral late-onset cataract
• Muscle weakness, stiffness & myotonia
• Low motivation, bowel probs, diabetes mellitus
• Heart block
• Death post-anaesthetic a risk if not monitored
• Congenital myotonic dystrophy
• Death / severe muscle disorder and learning difficulty