Dermatology Genetics

Question 1

periungual fibromata (benign tumour composed of fibrous / connective tissue) (which in this case is periungual = “around the nail”) can be due to?

Answer 1

Trauma – if there is just one.

BUT if there are multiple –> person could have tuberous sclerosis.

Question 2

what is tuberous sclerosis?

Answer 2

one of the most common genodermatoses.
It is a genetic disorder characterised by hamartomas in many organs. May have skin lesions, epileptic seizures, developmental delay. Severity varies widely.
May present as infantile seizures, earliest cutaneous sign is ash-leaf macule.
Autosomal dominant BUT new mutations are common.

Question 3

what are ash-leaf macules and what is their significance?

Answer 3

they are depigmented macules which are found in 90% cases of tuberous sclerosis. Can be hard to spot in pale-skinned people - so can use a Wood’s lamp to spot it.

Question 4

what tumours may be present in tuberous sclerosis?

Answer 4

periungual fibromas
facial angiofibromas
hamartomas
bone cysts
cortical tubers

Question 5

what is a hamartoma?

Answer 5

an overgrowth of normal tissue - not malignant or benign

Question 6

what are angiofibromas?

Answer 6

non cancerous tumours composed of fibrous tissue and blood vessels - they chiefly occur in nasal cavities and upper throat (but it is FACIAL angiofibromas which are likely to occur in tuberous sclerosis - these are pinky red spots in a butterfly distribution across the face).

Question 7

aside from ash-leaf macules, what are 2 other skin signs of tuberous sclerosis?

Answer 7

shagreen patches (areas of thick, leathery skin which are dimpled like orange peel)
enamel pitting in teeth

Question 8

cortical tubers can be found in tuberous sclerosis. What is their significance?

Answer 8

they can cause epilepsy, and varying degrees of mental impairment

Question 9

tuberous sclerosis is autosomal dominant/ recessive?

Answer 9

autosomal dominant (but new mutations are common). There are mutations in genes coding for tuberin and hamartin

Question 10

why does an older father increase the chance of new mutations?

Answer 10

the older the father, the more mutations his sperm have been through

Question 11

what does variable expressivity of genetic diseases mean?

Answer 11

means that disease severity can be variable

Question 12

what does variable penetrance of genetic diseases mean?

Answer 12

means that individuals with the mutation may not show the disease

Question 13

what is epidermolysis bullosa?

Answer 13

group of genetic skin fragility conditions, which could be dominant/ recessive/ new mutation/ acquired (as an autoimmune disease)
there is variable severity - some have blistering at birth, some present as adults.
Blistering at birth does NOT determine the prognosis

Question 14

what are the 3 types of epidermolysis bullosa?

Answer 14

• SIMPLEX EB (the keratinocyte integrity is affected - so get fragile blisters)
• JUNCTIONAL EB (mutation is at the DEJ)
• DYSTROPHIC EB (mutation is at the dermis, so damage here induces scarring (like there would be in surgery of a 3rd degree burn)

Question 15

sometimes in epidermolysis bullosa, the digits end up looking like a mitten. Why is this?

Answer 15

every time the hand is traumatised, it heals with a scar - the digits eventually are fused together and left like a mitten

Question 16

what is the acquired form of EB?

Answer 16

it’s a rare autoimmune disease - usually presents in adult life, and tends to be localised to areas which are easily damaged e.g. hands, feet, buttocks

Question 17

what is haploinsufficiency?

Answer 17

when a diploid organism has only a single functional copy of a gene (other copy is inactivated by a mutation) and so the single functional copy doesn’t produce enough gene product to bring about normality, and so causes an abnormal/ diseased state. (can be contrasted with haplosufficiency - where the single, unmutated allele can produce enough gene product to maintain the wild-type phenotype without the other allele)

Question 18

what is a dominant negative disease mechanism?

Answer 18

when there is a mutated gene that acts antagonistically to the wild-type (normal) allele - causing the normal protein to stop working

Question 19

what is a gain of function mutation?

Answer 19

when the mutant protein gains a new function - affecting cell processes

Question 20

what is a complete loss of protein?

Answer 20

autosomal recessive - 2 faulty copies of gene produce NO protein

Question 21

what are café au lait macules? what is their significance?

Answer 21

common birthmarks, presents as hyperpigmented skin patches with a sharp border. Usually present at birth/ appear in early infancy. Sun darkens them. More than 3 are uncommon, and more than 5 suggests genetic disease!!! café au lait macules have excessive numbers of melanosomes, produced by normal numbers of epidermal melanocytes.

Question 22

what is neurofibromatosis type 1?

Answer 22

genetic disorder that affects the bone, soft tissue, skin, and nervous system. Characterised by:

• 6 or more café au lait macules
• multiple neurofibromas (tumours, on, or hanging off, the skin)
• freckling (under armpits, areas of skin folds)
• Lisch nodules (tiny tumours of the iris)

Question 23

in atopic eczema, there is a mutation in the _____ gene?

Answer 23

filaggrin

Question 24

in atopic eczema, the mutation in the filaggrin gene causes ichthyosis vulgaris. What is ichthyosis vulgaris?

Answer 24

ichthyosis vulgaris is excessive, dry scaly skin. It’s the most common of the inherited ichthyoses (which are skin disorders characterised by rough, scaly skin). Ichthyosis vulgaris results from loss-of-function mutations in the gene encoding filaggrin. Atopic eczema is present in 50% people with ichthyosis vulgaris

Question 25

what is the significance of filaggrin?

Answer 25

filaggrin is required for the binding of keratin fibres in epidermal cells - to form an effective skin barrier. Xerosis (dry skin) results from reduced skin hydration associated with defective filaggrin.