multisystem disease Flashcards

1
Q

mode of inheritance in multi-system disorders

A

all possible modes of inheritance - new mutations or inherited
chromosomal
single gene disorders
multifactorial

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

mode of inheritance in multi-system disorders - chromosomal

A

numerical e.g. trisomy 21

structural e.g. translocations, deletions, micro-deletions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

mode of inheritance in multi-system disorders - single gene disorders

A

autosomal dominant - TS, NF1, myotonic dystrophy
autosomal recessive - CF
- X linked - Duchenne muscular dystrophy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

mode of inheritance in multi-system disorders - multifactorial

A

polygenic

environmental - haemochromatosis, diabetes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what causes multisystem involvement

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

common problems in multisystem disease

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

alternative name for neurofibromatosis type 1

A

Von Recklinghausen disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

inheritance of NF1

prevalence

A

autosomal dominant

1/3500

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

NIH diagnostic criteria for NF1

A

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what are these

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what are these

A

cutaneous neurofibromas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what are these

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what are these

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

further features of NF1

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is this

A

tibial dysplasia (pseudoarthrosis)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

genetics of NF1

A

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

17
Q

how is NF1 diagnosed

A

clinical diagnosis using diagnostic criteria

18
Q

management of NF1

A
  • 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)
19
Q

NF2 features

gene affected

A

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

19
Q

NF2 features

gene affected

A

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

20
Q

tuberous sclerosis incidence

A

1/7000 newborns

21
Q

classic triad in TS

A

epilepsy - young onset, difficult to treat
learning difficulty
skin lesions

also hamartomas in different organs

22
Q

genetics of TS

A

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

23
Q

clinical features of TS

A

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

24
what are these
angiofibromas typically perioral and across the bridge of the nose (butterfly shaped rash)
25
what are these
subungual fibroma lump and ridge in the nail can also appear as a channel in the nail
26
what feature of TS is seen here
cortical tubers sub-ependymal nodules astrocytoma can be the basis for epilepsy
27
what feature of TS is this
retinal phakoma usually stable and don't require intervention
28
TS - brain clinical features
90% epilepsy 80-90% SEN - special educational needs 10-15% SEGA - Subependymal giant cell astrocytoma 90% TAND - TSC associated neuropsychiatric disorders 50% intellectual disability 40% ASD
29
TS - heart clinical features
INFANTS - 90% cardiac rhabdomyoma | ADULTS - 20% cardiac rhabdomyoma
30
TS - kidney clinical features
70% angiomyolipoma 35% simple multiple cysts 4% PCKD 2-3% renal cell carcinoma
31
TS - skin clinical features
``` 75% angiofibroma 20-80% ungual fibroma 25% fibrous cephalic plaques >50% shagreen patches 90% focal hypopigmentation ```
32
TS - lung clinical features
WOMEN 80% asymptomatic LAM - Lymphangioleiomyomatosis 5-10% symptomatic LAM - can lead to resp failure MEN AND WOMEN 10% MMPH - Multifocal micronodular pneumocyte hyperplasia
33
TS - facial clinical features
50% oral fibromas | 50% retinal astrocytic hamartomas
34
screening of at risk relatives for TS
siblings and parents may be mildly affected surveillance and genetic counselling clinical examination - skin signs, incl Woods lamp for pale patches, nails, retinal examination cranial MRI renal US Echo
35
facial features of myotonic dystrophy
myopathic appearance of the face | weak muscles - saggy mouth, drooping eyelids
36
commonly affected muscles in myotonic dystrophy
weakened distal muscles daphragm
37
genetics of myotonic dystrophy
autosomal dominant | CTG repeat - exhibits anticipation with increasing severity in each generation
38
features of myotonic dystrophy
``` bilateral late onset cataract myscle weakness, stiffness and myotonia low motivation, bowel problems, DM heart block risk of death post-anaesthesia if not monitored ``` congenital myotonic dystrophy - death/severe muscle disorder and learning difficulty