SM 259: Genetic Disease

Question 1

What are Genodermatoses?

Answer 1

Monogenetic skin disorders that present before adulthood

Question 2

What often leads to diagnosis of a Genodermatoses?

Answer 2

A skin manifestation, allowing for early counseling and intervention

Question 3

What are Ichthyoses?

Answer 3

A group of dozens of disorders characterized by abnormal epidermal cell maturation leading to a poor epidermal barrier

Question 4

Why do Ichythoses have skin thickening?

Answer 4

Skin thickens and scales to compensate for poor barrier function

Question 5

What is Keratin?

Answer 5

The major protein of Keratinocytes in the epidermal barrier

Question 6

What is found in the Stratum Granulosum?

Answer 6

Keratinocytes filled with Filaggrin granules

Question 7

What does Filaggrin do?

Answer 7

Promotes cell flattening and enables crosslinking by Transglutaminase

Also breaks down into products that maintain skin hydration

Question 8

What is Ichthyosis vulgaris?

Answer 8

Most common Ichythyoses, due to null mutations in Profilaggrin that leads to reduced levels of Filaggrin

Mutations vary by racial group but have the same outcome

Question 9

Where does scaling occur in Ichthyosis?

Answer 9

Lower extremities mostly, and hyperlinear palms

Question 10

Why is Icythyoses considered semidominant in null filaggrin mutations?

Answer 10

Losing one allele causes scales, but losing both causes a much more severe lethal phenotype

Question 11

When is Ichthyoses more common?

Answer 11

Worse in the winter

Question 12

What conditions is Ichthyoses associated with?

Answer 12

Atopic Dermatis and Keratosis Pilaris

Question 13

What does Ichthyoses vulgaris lead to?

Answer 13

Dry skin from water loss and easier triggering of immune reactivity, if they have less Filaggrin, such as allergies

Question 14

What is X-linked recessive Ichthyosis?

Answer 14

A form of Ichthyosis that is due to a deletion in Arylsulfatase C, leading to accumulation of Cholesterol Sulfate

Question 15

What molecule accumulates in X-linked recessive Ichthyosis and why is this significant?

Answer 15

A defect in Arylsuflatase C leads to an accumulation of Cholesterol Sulfate, which inhibits normal degradation of Stratum Corneum Desmosomes and causes retention of scale

Question 16

When does X-linked recessive Ichthyosis present and how?

Answer 16

Within the first 3 months of life, with generalized scaling that spares the flexural areas as well as the face

Question 17

What are Collodion babies?

Answer 17

Babies born with a saran-like membrane due to an autosomal recessive congenital icthyosis

Question 18

What is Lamellar Ichthyosis?

Answer 18

A disease characterized by deficient Transglutaminase 1, which prevents the maturation and shedding of Epidermis

Question 19

What is Congenital Icthyosiform Erythroderma?

Answer 19

A predominant erythroderma with finer scaling due to defects in Lipoxygenase pathways

Question 20

What is Epidermolytic Ichthyosis?

Answer 20

An Autosomal Dominant disease that causes superficial blisters at birth and later warty skin thickening to compensate from blistering

Question 21

What are Keratins?

Answer 21

Intermediate filament proteins that provide structural integrity to the epidermal cell

Question 22

What is Mosiac Epidermolytic Icthyosis?

Answer 22

A mutation in Keratin genes in some but not all cells that leads to a patterned scaling

Question 23

What pattern does the scaling in Mosaic Epidermolytic Icthyosis follow?

Answer 23

Blachko’s lines of embroylogic development

Question 24

What determines how a Keratinopathy presents?

Answer 24

The features of a Keratinopathy depends on the tissues in which the mutated Keratin gene is expressed

Question 25

What is Epidermolysis Bullosa?

Answer 25

An autosomal dominant disorder caused by mutations in the Keratin genes

Question 26

What is Junctional EB and what does i tlead to?

Answer 26

An autosomal recessive disorder with generalized blistering due to missing components of the Hemidesmosome, leading to early demise

Question 27

What does the Hemidesmsome do?

Answer 27

Binds Epidermis to Dermis, and the loss of Hemidesmosome can lead to Junctional EB

Question 28

What are the two types of Dystrophic EB?

Answer 28

Autosomal dominant and Autosomal recessive

Question 29

What is AD Dystrophic EB?

Answer 29

Due to a missense mutation in a Collagen gene, leads to blistering and scarring at sites of trauma

Question 30

What is AR Dystrophic EB?

Answer 30

Due to mutations on both Collagen alleles, causing severe generalized blistering of skin and growth retardation

Question 31

Are tumor syndromes autosomal dominant or recessive?

Answer 31

Autosomal dominant

Question 32

How do tuor syndromes arise from signalling and oncogenes?

Answer 32

Insufficient inhibition of tumor oncogenes and activation of signaling pathways

Question 33

What does a loss of heterozygosity refer to in a tumor syndrome?

Answer 33

Second mutation in a previously normal allele leads to tumor formation

Question 34

What causes Neurofibromatosis and how do they present?

Answer 34

AD, deletion in Neurofibromin tumor suppresor gene leads to RAS activation and cuases Lisch nodules + Cafe au lait spots

Question 35

What causes tumors in NF-1 and what do they lead to?

Answer 35

Tumors in NF-1 arise from loss of heterozygosity and cause optic gliomas and plexiform neurofibroma

Question 36

What causes Basal Cell Nevus Syndrome and how does it present?

Answer 36

AD, due to mutations in patched gene causing loss of heterozygosity and leading to medulloblastomas in young children with cysts of jaw and skin

Question 37

What causes Tuberous Sclerosis and how does it present?

Answer 37

AD, mutations in TSC1/2, leading to seizures, astrocytomas, and collagenomas

Question 38

What is Whole Exome Sequencing?

Answer 38

Unbiased approach, using simultaneous analysis of all cnadidate genes

Question 39

How can diagnosis be made prenatally?

Answer 39

Amniocentesis and Chorionic Villus Sampling

Question 40

How can a normal baby be guaranteed?

Answer 40

IVF with only a normal egg

Question 41

How can recombinant proteins treat skin disorders?

Answer 41

Add a missing protein to fix a disorder

Question 42

How can a gene with a mutation be skipped?

Answer 42

Use Aminoglycosides to skip exons with null mutations

Question 43

How can skin cells with a gene mutation be corrected?

Answer 43

Gene therapy to correct skin cells by using a viral vector to implant a normal gene and graft back healthy skin

Question 44

How can gene suppression fix a skin disorder?

Answer 44

Knockout a mutated protein with siRNA

Question 45

What benefit does CRISPR/Cas have?

Answer 45

CRISPR/Cas can clear bad genes and fix them with dsDNA breaks and Homology Directed Repair using a normal sequence template

Question 46

What can Rapamycin be used to treat?

Answer 46

Tuberous Sclerosis, since it’s an mTOR inhibitor

Question 47

What can Hedgehog inhibitors be used to treat?

Answer 47

BCNS