Multi-System Diseases

Question 1

What are the modes of inheritance in multi-system disorders?

Answer 1

Chromosomal
Single gene disorders
Multifactorial

Question 2

What is included in chromosomal mode of inheritance?

Answer 2

Numerical - trisomy 21
Structural - translocations, deletions and microdeletions

Question 3

What is included in single gene disorders modes of inheritance?

Answer 3

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

Question 4

What is included in multifactorial modes of inheritance?

Answer 4

Polygenic
Environmental factors - haemochromatosis and diabetes

Question 5

Why is there multi-system involvement?

Answer 5

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 6

What are common problems in multi-system disease?

Answer 6

Variable expression within as well as between families - difficulty to predict phenotype from genotype
Present to a large variety of different specialists
FH easily missed

Question 7

Is neurofibromatosis type 1 (NF1) autosomal dominant or recessive?

Answer 7

Autosomal dominant

Question 8

What is the NIH diagnostic criteria for NF1?

Answer 8

Cafe au lait spots - 6 or more
Neurofibromas - 2 or more
Axillary freckling
Lisch nodules - specks in iris
Optic glioma
Thinning of long bone cortex
FH

Question 9

What are some further features of NF1?

Answer 9

Macrocephaly, short stature, dysmorphic features, learning difficulties, epilepsy, scoliosis, pseudarthrosis of the tibia, raised BP and neoplasia

Question 10

What is the management of NF1?

Answer 10

Annual review of affected individuals
BP, spine for scoliosis, tibia for unusual angulation, visual acuity, visual fields and educational assessment

Question 11

Describe the genetics of NF1

Answer 11

Autosomal dominant
Variable expression
Gene identified - 17q
Mutations different in different families
50% due to new mutations

Question 12

What are the main features of NF2?

Answer 12

Acoustic neuromas - usually bilateral
CNS and spinal tumours
A few CAL spots
Is on chromosome 22

Question 13

What is the classical triad of tuberous sclerosis complex (TSC)?

Answer 13

Epilepsy, learning difficulty and skin lesions

Question 14

What is tuberous sclerosis complex?

Answer 14

Autosomal dominant
Incidence 1 in 1000 newborns
Hamartomas in different organs

Question 15

What are the genetics of TSC?

Answer 15

Autosomal dominant
Variable expression
Almost full penetrance - gene carriers will have some signs even if only on scans
TSC1 and TSC2 - 2 genes on different chromosomes

Question 16

What are the classical features of TSC?

Answer 16

Multi-system
Variable expression - asymptomatic to severe mental and occasionally physical handicap
Learning difficulty - autistic features common
Seizures

Question 17

What are some other features of TSC?

Answer 17

Skin lesions - depigmented macules, angiofibroma, fibrous plaque forehead, shagreen patches and ungual fibromas
Kidney - cysts and angiomyolipomata
Phakomas in eye
Rhabdomyomas in heart

Question 18

Describe screening at-risk relatives

Answer 18

Siblings and parents may be mildly affected
Surveillance and genetic counselling
Genetic testing key
Clinical examination
Cranial MR scan
Renal US
Echo

Question 19

What is myotonic dystrophy?

Answer 19

Autosomal dominant
CTG repeat, exhibits anticipation with increasing severity in each generation

Question 20

What are some features of myotonic dystrophy?

Answer 20

Bilateral late-onset cataract
Muscle weakness, stiffness and myotonia
Low motivation, bowel problems and DM
Heart block
Death post-anaesthetic
Congenital myotonic dystrophy