Multi-system Disease

Question 1

What are the modes of inheritance of multi system disorders?

Answer 1

Chromosomal
Singel gene disorders (autosomal dominant, recessive or X linked)
Multifactoral (polygenic, environmental factors)

Question 2

How does multi-system involvement occur?

Answer 2

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

Question 3

What mode of inheritance causes neurofibromatosis type 1 (NF1)?

Answer 3

Autosomal dominant

Question 4

What is the diagnostic criteria for NF1?

Answer 4

2+ for diagnosis: 
Cafe au last 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 5

What other features are associated with NF1?

Answer 5

Macrocephaly 
Short stature 
Dysmorphic features "Noonan look" 
Learning difficulties 
Epilepsy 
Scoliosis 
Pseudoarthritis of tibia 
Raised BP (renal artery stenosis/ phaechromocytoma) 
Neoplasia

Question 6

What is the management of NF1?

Answer 6

Annual review or affected individuals and at risk children until diagnosis can be excluded 
BP 
Spine for scoliosis 
Tibia for unusual angulation 
Visual acuity and visual field

Question 7

What gene is identified as part of NF1?

Answer 7

17q

Question 8

What are the main features of NF2?

Answer 8

Acoustic neuromas, usually bilateral
CNS and spinal tumours
A few CAL spots

Question 9

Where is the NF2 gene found?

Answer 9

Chromosome 22

Question 10

What mode of incidence causes tuberous sclerosis (TS)?

Answer 10

Autosomal dominant

Question 11

What genes are responsible for causing TS?

Answer 11

TSC1
TSC2
Both have identical phenotypes

Question 12

What is the classic triad of TS?

Answer 12

Epilepsy
Learning difficulty
Skin lesions

Question 13

What are the clinical features of TS?

Answer 13

Learning difficulty (autistic features common)
Seizures (infantile spasms, myoclonic seizures)
Asymptomatic

Question 14

What skin features can be present with TS?

Answer 14

Depigmented macules 
Angiofibromas 
Fibrous plaque forehead 
Shagreen patches 
Ungual fibromas

Question 15

What other features can present with TS?

Answer 15

Kidney (cysts and angiomyolipomata)
Phakomas in eye
Rhabdomyomas in heart

Question 16

What investigations should be considered for screening at risk relatives for TS?

Answer 16

Clinical examination (skin signs, Wood’s lamp, nails, retinal examination)
Cranial MR scan
Renal USS
Echocardiogram

Question 17

What mode of incidence causes myotonic dystrophy?

Answer 17

Autosomal dominant

Question 18

What are the clinical features of myotonic dystrophy?

Answer 18

Bilateral late-onset cataract 
Muscle weakness, stiffness and myotonia 
Low motivation 
Bowel problems 
Diabetes 
Heart block 
Death post-anaesthetic a risk

Question 19

What is the gene involvement of myotonic dystrophy?

Answer 19

CTG repeat, exhibits anticipation with increasing severity in each generation