Dermatology-genetics: Clinical Cases and Genetic Mechanisms

Question 1

What 2 clinical signs can be seen?

Answer 1

Periungual fibromata (smooth, firm, flesh-coloured lumps that emerge from the nail folds and are more common on the toenails)

Longitudinal ridging

Question 2

A 35 year old woman has these two clinical signs along with epilepsy (since 7 years of age) and normal intelligence.

What is the diagnosis?

Answer 2

Tuberous Sclerosis

Question 3

What is tuberous sclerosis?

Answer 3

One of the most common genodermatoses and is characterised by hamartomas in many organs, part. the skin, brain, eye, kidney and heart

Question 4

What are hamartomas?

Answer 4

AKA angiomyolipomas:

Non-cancerous malformations composed of overgrowth of the cells and tissues

Question 5

Inheritance of Tuberous Sclerosis?

Answer 5

Autosomal dominant but new mutations are COMMON

Question 6

Earliest cutaenous sign of tuberous sclerosis?

Answer 6

Ash-leaf macules (depigmented macules found in 90% of TS cases); these can occur without the person having TS but it is abnormal if many develop

Question 7

How to confirm presence of ash leaf macules?

Answer 7

Skin is examined while exposed to Wood’s lamp

Question 8

Presentation of tuberous sclerosis?

Answer 8

Periungual fibromas

Facial angiofibromas (rash that appears as a spread of small pink/red spots across the cheeks and nose in a butterfly distribution; starts to develop in the first few years of life before worsening)

Seizures and varying degrees of mental impairment (cortical tubers and/or calcification of falx cerebri)

Bone cysts may be seen on X-ray

Shagreen patches (flesh coloured, orange-peel connective tissue naevi of varying sizes, usually on the lower back)

Enamel pitting

Question 9

Gene mutations causing TS?

Answer 9

Mutation in one of two genes:

TSC1 (produces hamartin; chromosome 16)

TSC2 (produces tuberin; chromosome 9)

Question 10

What is the risk of an affected child if the parent is affected?

Answer 10

50%

Question 11

Severity of disease?

Answer 11

Penetrance is variable (but high), i.e: some people do not show features of the disease

Disease expression is variable, i.e: different people are affected differently, even within the same family

Question 12

Gender most likely to be affected by TS?

Answer 12

Males and females equally likely

Question 13

Types of mutations that cause TS?

Answer 13

Many different mutations can cause TS, e.g: missense, deletion (in frame), premature stop, deletion (frameshift)

Question 14

Treatment option due to understanding of the pathway?

Answer 14

mTOR inhibitors

Question 15

TS displays genetic heterogenicity?

Answer 15

Single phenotype or genetic disorder may be caused by any one of a multiple number of alleles or non-allele (locus) mutations, i.e: for TS, the mutation may be in TSC1 or TSC2

Question 16

On this graph, in which group does TS belong in?

Answer 16

Mendelian disorders

Question 17

What is epidermolysis bullosa (EB)?

Answer 17

Group of skin fragility conditions characterised by blistering lesions on the skin and mucous membranes

They can be autosomal dominant or recessive, could be a new mutation or acquired

Question 18

Severity of EB?

Answer 18

Variable - blistering at birth does not determine prognosis

Question 19

Three main types of epidermolysis bullosa (EB)?

Answer 19

EB simplex - affects the epidermis

EB junctional - affects the lamina lucida within the DEJ

EB dystrophic - affects the lamina densa and deeper into the dermis

Question 20

Feature of EB dystrophic?

Answer 20

Blistered fingers heal with scarring; fingers begin to fuse

Question 21

Genes involved with EB?

Answer 21

>20 genes are involved and they affect skin structure and adhesion, e.g:

Keratin 5 and 14

Laminins

Integrins

Collagen 17

Question 22

What is EB acquisita?

Answer 22

Rare autoimmune condition (acquired) where an Ab attacks collagen 17

Question 23

What is the dominant-negative disease mechanism of EB?

Answer 23

Mutant gene and expression of abnormal protein interfere with normal protein

Question 24

What is the haploinsufficiency disease mechanism (dominant) in EB?

Answer 24

Mutant gene produces nothing and so LESS PROTEIN OVERALL is produced, as only one copy is working

Question 25

What happens in autosomal recessive disease of EB?

Answer 25

Both genes are mutated and produce NO PROTEIN

Often only one generation is affected and there is a 1/4 risk of an affected child being born if the parents are carriers; likelihood is increased in consanguineous families

Question 26

What happens when there is a gain in the mutant protein?

Answer 26

Mutant protein gains a new function, affecting cell processes

Question 27

What is this clinical sign called?

Answer 27

Cafe au lait macules - asymptomatic, coffee-coloured macules Some people have 1/2 normally but >5 suggests a genetic disease

Question 28

Two clinical signs in this image?

Answer 28

Cafe-au lait macules

Neurofibromas (soft neural tumours)

Question 29

What is neurofibromatosis?

Answer 29

Genetic disorder affecting bone, soft tissue, skin and nervous system

Two types:

Neurofibromatosis 1 (NF1)

Neurofibromatosis 2 (NF2)

Question 30

Other clinical features of NF1?

Answer 30

Plexiform neuroma (diffuse) - invasive tumours that may involve all layers of skin, muscle, bone and blood vessels

Axillary or inguinal freckling (abnormal in sun-protected sites)

Optic glioma - malignant tumour of the glial tissue of the optic nerve

2 or more Lisch nodules (tiny tumours on iris of eye)

Distinctive bony lesion

Question 31

Treatment of neurofibromatosis based on the pathway?

Answer 31

MEK inhibitors

Question 32

3 factors contributing to eczema?

Answer 32

Skin barrier function (affected by genetic factors, e.g: fillagrin - AKA filament aggregating gene - is a skin barrier gene)

Environmental factors

Immunology (affected by genetic factors, e.g: IL-4, IL-13)

Question 33

What is ichthyosis vulgaris?

Answer 33

Autosomal dominant disorder of cornification, characterised by persistently dry, thickened, “fish scale” skin

Children will have HYPERLINEAR PALMS

Question 34

Mutations in fillagrin increase the risk of which conditions?

Answer 34

Of eczema:

4x Asthma

Hay fever 3x

Peanut allergy 5x

Question 35

How do genes play a role in common diseases?

Answer 35

Become risk factors