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Y3 - genetics > multisystem disease > Flashcards

multisystem disease Flashcards

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1
Q

mode of inheritance in multi-system disorders

A

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

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2
Q

mode of inheritance in multi-system disorders - chromosomal

A

numerical e.g. trisomy 21

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

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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

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4
Q

mode of inheritance in multi-system disorders - multifactorial

A

polygenic

environmental - haemochromatosis, diabetes

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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

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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

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7
Q

alternative name for neurofibromatosis type 1

A

Von Recklinghausen disease

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8
Q

inheritance of NF1

prevalence

A

autosomal dominant

1/3500

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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
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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

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11
Q

what are these

A

cutaneous neurofibromas

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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

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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

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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
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15
Q

what is this

A

tibial dysplasia (pseudoarthrosis)

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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
Q

what are these

A

angiofibromas

typically perioral and across the bridge of the nose (butterfly shaped rash)

25
Q

what are these

A

subungual fibroma

lump and ridge in the nail
can also appear as a channel in the nail

26
Q

what feature of TS is seen here

A

cortical tubers
sub-ependymal nodules
astrocytoma

can be the basis for epilepsy

27
Q

what feature of TS is this

A

retinal phakoma

usually stable and don’t require intervention

28
Q

TS - brain clinical features

A

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
Q

TS - heart clinical features

A

INFANTS - 90% cardiac rhabdomyoma

ADULTS - 20% cardiac rhabdomyoma

30
Q

TS - kidney clinical features

A

70% angiomyolipoma
35% simple multiple cysts
4% PCKD
2-3% renal cell carcinoma

31
Q

TS - skin clinical features

A 
75% angiofibroma 
20-80% ungual fibroma 
25% fibrous cephalic plaques
>50% shagreen patches
90% focal hypopigmentation
32
Q

TS - lung clinical features

A

WOMEN
80% asymptomatic LAM - Lymphangioleiomyomatosis
5-10% symptomatic LAM - can lead to resp failure

MEN AND WOMEN
10% MMPH - Multifocal micronodular pneumocyte hyperplasia

33
Q

TS - facial clinical features

A

50% oral fibromas

50% retinal astrocytic hamartomas

34
Q

screening of at risk relatives for TS

A

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
Q

facial features of myotonic dystrophy

A

myopathic appearance of the face

weak muscles - saggy mouth, drooping eyelids

36
Q

commonly affected muscles in myotonic dystrophy

A

weakened distal muscles

daphragm

37
Q

genetics of myotonic dystrophy

A

autosomal dominant

CTG repeat - exhibits anticipation with increasing severity in each generation

38
Q

features of myotonic dystrophy

A 
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

Y3 - genetics (3 decks)

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