Dermatology-genetics: Clinical Cases and Genetic Mechanisms Flashcards
What 2 clinical signs can be seen?
Periungual fibromata (smooth, firm, flesh-coloured lumps that emerge from the nail folds and are more common on the toenails)
Longitudinal ridging
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?
Tuberous Sclerosis
What is tuberous sclerosis?
One of the most common genodermatoses and is characterised by hamartomas in many organs, part. the skin, brain, eye, kidney and heart
What are hamartomas?
AKA angiomyolipomas:
Non-cancerous malformations composed of overgrowth of the cells and tissues
Inheritance of Tuberous Sclerosis?
Autosomal dominant but new mutations are COMMON
Earliest cutaenous sign of tuberous sclerosis?
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
How to confirm presence of ash leaf macules?
Skin is examined while exposed to Wood’s lamp
Presentation of tuberous sclerosis?
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
Gene mutations causing TS?
Mutation in one of two genes:
TSC1 (produces hamartin; chromosome 16)
TSC2 (produces tuberin; chromosome 9)
What is the risk of an affected child if the parent is affected?
50%
Severity of disease?
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
Gender most likely to be affected by TS?
Males and females equally likely
Types of mutations that cause TS?
Many different mutations can cause TS, e.g: missense, deletion (in frame), premature stop, deletion (frameshift)
Treatment option due to understanding of the pathway?
mTOR inhibitors
TS displays genetic heterogenicity?
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
On this graph, in which group does TS belong in?
Mendelian disorders
What is epidermolysis bullosa (EB)?
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
Severity of EB?
Variable - blistering at birth does not determine prognosis
Three main types of epidermolysis bullosa (EB)?
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
Feature of EB dystrophic?
Blistered fingers heal with scarring; fingers begin to fuse
Genes involved with EB?
>20 genes are involved and they affect skin structure and adhesion, e.g:
Keratin 5 and 14
Laminins
Integrins
Collagen 17
What is EB acquisita?
Rare autoimmune condition (acquired) where an Ab attacks collagen 17
What is the dominant-negative disease mechanism of EB?
Mutant gene and expression of abnormal protein interfere with normal protein
What is the haploinsufficiency disease mechanism (dominant) in EB?
Mutant gene produces nothing and so LESS PROTEIN OVERALL is produced, as only one copy is working
What happens in autosomal recessive disease of EB?
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
What happens when there is a gain in the mutant protein?
Mutant protein gains a new function, affecting cell processes
What is this clinical sign called?
Cafe au lait macules - asymptomatic, coffee-coloured macules Some people have 1/2 normally but >5 suggests a genetic disease
Two clinical signs in this image?
Cafe-au lait macules
Neurofibromas (soft neural tumours)
What is neurofibromatosis?
Genetic disorder affecting bone, soft tissue, skin and nervous system
Two types:
Neurofibromatosis 1 (NF1)
Neurofibromatosis 2 (NF2)
Other clinical features of NF1?
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
Treatment of neurofibromatosis based on the pathway?
MEK inhibitors
3 factors contributing to eczema?
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)
What is ichthyosis vulgaris?
Autosomal dominant disorder of cornification, characterised by persistently dry, thickened, “fish scale” skin
Children will have HYPERLINEAR PALMS
Mutations in fillagrin increase the risk of which conditions?
Of eczema:
4x Asthma
Hay fever 3x
Peanut allergy 5x
How do genes play a role in common diseases?
Become risk factors
