Genetics of multi system disorders

Question 1

Which mode of inheritance for trisomy 21?

Answer 1

Chromosomal

Question 2

Which mode of inheritance for TS?

Answer 2

Autosomal dominant

Question 3

Which mode of inheritance for NF1?

Answer 3

Autosomal dominant

Question 4

Which mode of inheritance for Myotonic dystrophy?

Answer 4

Autosomal dominant

Question 5

Which mode of inheritance for cystic fibrosis?

Answer 5

Autosomal recessive

Question 6

Which mode of inheritance for Duchenne muscular dystrophy?

Answer 6

X-linked

Question 7

Types of Chromosomal disorders?

Answer 7

> Numerical eg trisomy 21

> Structural eg translocations, deletions and micro deletions

Question 8

Types of single gene disorders?

Answer 8

> Autosomal dominant eg TS, NF1, myotonic dystrophy

> Autosomal recessive eg Cystic fibrosis

> X-linked eg Duchenne muscular dystrophy

Question 9

Types of multifactorial disorders?

Answer 9

> Polygenic

> Environmental factors:

- Haemochromatosis
- Diabetes

Question 10

Why multi-system involvement?

Answer 10

1) Several genes with diverse functions are involved (chromosomal)
2) Single gene widely expressed in different tissues
3) Single gene tissue-specific expression but tissue integral part of many different systems

Question 11

Common problems in multi-system disease?

Answer 11

1) Variable expression within as well as between families
2) Present to a large variety of different specialists
3) Family history easily missed

Question 12

What is the inheritance of neurofibromatosis type 1 (NF1)?

Answer 12

Autosomal Dominant

Question 13

What is the prevalence of neurofibromatosis type 1 (NF1)?

Answer 13

Prevalence 1/2500-3500

Question 14

What is the diagnostic criteria for neurofibromatosis type 1 (NF1)?

Answer 14

Requires 2 or more:
1) Café au lait spots - 6 or more
2) Neurofibromas - 2 or more
axillary freckling
3) Lisch nodules (specks in iris) 
4) Optic glioma
5) Thinning of long bone cortex
6) Family history

Question 15

Features of neurofibromatosis type 1 (NF1)?

Answer 15

1) Café au lait spots - 6 or more

2) Neurofibromas - 2 or more
axillary freckling

3) Lisch nodules (specks in iris)
4) Optic glioma
5) Thinning of long bone cortex
6) Macrocephaly
7) Short stature
8) Dysmorphic features- “Noonan look”
9) Learning difficulties
10) Epilepsy
11) Scoliosis
12) Pseudoarthrosis of the tibia
13) Raised BP - due to renal artery stenosis or phaechromocytoma
14) Neoplasia - CNS (optic gliomas), endocrine

Question 16

Management of neurofibromatosis type 1 (NF1)?

Answer 16

> 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 17

Which gene is the cause of neurofibromatosis type 1 (NF1)?

Answer 17

Loss or mutation of 17q - A tumour suppressor gene

Question 18

50% of cases of neurofibromatosis type 1 (NF1) are due to new mutations, what is the origin usually?

Answer 18

Usually paternal in origin

Question 19

What are the main features of neurofibromatosis type 1 (NF2)?

Answer 19

1) Acoustic neuromas - usually bilateral
2) CNS and spinal tumours
3) A few CAL spots

Question 20

What is the mutation of NF2?

Answer 20

NF2 gene on chromosome 22

Question 21

What is the incidence of Tuberous Sclerosis (TS)?

Answer 21

1 in 7000

Question 22

What are the main features of tuberous sclerosis?

Answer 22

The classic triad:

1) Epilepsy, in 65%:
- Infantile spasms
- Myoclonic seizures

2) Learning difficulty in 40%:
- Autistic features are common

3) Skin lesions:
- Depigmented macules
- Angiofibromas
- Fibrous plaque forehead
- Shagreen patches
- Ungual fibromas
- Focal Hypopigmentation

Harmartomas in different organs:

• Kidney = Cysts and angiomyolipomata
• Phakomas in eye, benign unless on macula
• Heart = Rhabdomyomas
• CNS = Cortical tubers, sub-ependymal nodule, astocytomas

Question 23

What os the mode of inheritance of Tuberous sclerosis (TS)?

Answer 23

Autosomal dominant - 60% are due to new mutations

Almost full penetrance - Gene carriers will have some signs even if only on scans

Question 24

What is meant by variable expression in Tuberous sclerosis?

Answer 24

Severity varies between family members

Question 25

Which genes are the cause of Tuberous Sclerosis?

Answer 25

2 genes on different chromosomes both cause TS with identical phenotypes:
> TSC1
> TSC2

Question 26

Clinical examination in Tuberous sclerosis (Screening tools)?

Answer 26

> Skin signs, including Woods lamp, nails

> Retinal examination

Question 27

Screening tools in Tuberous sclerosis?

Answer 27

1) Clinical examination
- Skin signs, including Woods lamp, nails
- Retinal examination
2) Cranial MR scan
3) Renal ultrasound
4) Echocardiogram

Question 28

Mode of inheritance for myotonic dystrophy?

Answer 28

Autosomal dominant

Question 29

Mutation which leads to myotonic dystrophy?

Answer 29

CTG repeat, exhibits anticipation with increasing severity in each generation

Question 30

Presentation features of myotonic dystrophy?

Answer 30

1) Bilateral late-onset cataract

2) Muscle weakness, stiffness & myotonia
- Facial features
- Trapezius, forearms, lower leg and diaphragm affected

3) Low motivation, bowel probs, diabetes mellitus
4) Heart block
5) Death post-anaesthetic a risk if not monitored

6) Congenital myotonic dystrophy:
- Death
- Severe muscle disorder
- Learning difficulty

Question 31

Things to remember in multi-system genetic disorders?

Answer 31

> Treat the whole patient

> Role for co-ordinating specialist

> Regular follow up if clinically beneficial

> Remember reproductive counselling

> Variable expression

> Understanding natural history allows early management of complications