SM_259a: Genetic Disease Update Flashcards
Genodermatoses are ____
Genodermatoses are monogenic genetic skin disorder
Epidermal barrier functions to ____ and ____
Epidermal barrier functions to prevent dessication and protect from routine and extreme environments
(antigens, toxins, detergents and solvents, UV light, microorganisms)
Ichthyoses are ____ that manifest as ____
Ichthyoses are heterogenous group of dozens of disorders with abnormal epidermal cell maturation leading to poor epidermal barrier and skin thickening and scaling to compensate for poor epidermal barrier function
Describe components of the epidermal barrier
Epidermal barrier components
- Bricks and mortar: cell bricks surrounded by lipids, major protein of keratinocytes is keratin
- Stratum corneum: directly faces external environment
- Stratum granulosum: keratinocytes filled with granules largely made of filaggrin
Filaggrin is found in the ____ and promotes ____ and enables ____ via ____ for insoluble barrier
Filaggrin is found in the stratum granulosum and promotes cell flattening and enables crosslinking via transglutaminase 1 for insoluble barrier
(filaggrin breakdown products keep skin hydrated)
Ichythosis vulgaris involves null mutations that reduce ____ and manifests as ____, ____, and ____
Ichythosis vulgaris involves null mutations that reduce filaggrin and manifests as scaling (especially on legs), worse in winter (weather, moisturizer dependent), and hyperlinear palms
(associated with atopic dermatitis and keratosis pilaris, leads to dry skin via water loss, and higher risk of asthma / hay fever / food and other allergies if filaggrin mutations and eczema are present)
X-linked recessive ichthyosis is usually caused by ____, leading to ____ accumulation and inhibition of ____, promoting ____
X-linked recessive ichthyosis is usually caused by deletion in ARSC1 (encodes arylsulfatase C = steroid sulfatase), leading to cholesterol sulfate accumulation and inhibition of normal degradation of stratum corneum desmosomes, leading to retention of scale
- Begins in first three months
(carrier mothers show no skin features but have prolonged delivery with failure to progress)
X-linked recessive begins in ___
X-linked recessive begins in first three months
Collodion babies are born with a ____ and are clinical manifestation of ____
Collodion babies are born with a saran-like membrane and are clinical manifestation of autosomal recessive congenital ichthyosis
(most commonly sheds in first month and shows lamellar ichthyosis -> congenital ichthyosiform erythdroderma -> other ichthyotic disorders)
Lamellar ichthyosis involves ___ deficiency in most patients, which is required for ___ and ___ of epidermis
Lamellar ichthyosis involves transglutaminase 1 deficiency in most patients, which is required for maturation and shedding of epidermis
Congenital ichthyosiform erythoderma involves ___ and can be caused by ___
Congenital ichthyosiform erythoderma involves predominant erythroderma with finer scaling and can be caused by mutation in 10 genes affecting barrier and inflammatory pathways (especially lipooxygenase, biallelic)
Epidermolytic ichthyosis involves ____ at birth and ____ to ____ and ____
Epidermolytic ichthyosis involves progressive warty skin thickening to compensate and protect from blistering and improve barrier
____ are intermediate filament proteins that provide structural integrity to the epidermal cell
Keratins are intermediate filament proteins that provide structural integrity to the epidermal cell
(specific keratin proteins pair to form keratin filament structure, mutations in KRT1 or KRT10)
Mosaic epidermolytic ichthyosis (epidermal nevus) involves a mutation in ____
Mosaic epidermolytic ichthyosis (epidermal nevus) involves a mutation in keratin 1 or 10 in some cells but not all cells
(all offspring cells of mutated cells show the same genotype and phenotype, scaling process is patterned)
Epidermal nevi follow ____
Epidermal nevi follow Blaschko’s lines of embryonic development of epidermal skin cells (keratinocytes)
Benign congenital or acquired nevi involve activated ____ or ____ pathways
Benign congenital or acquired nevi involve activated RAS-ERK or mTOR signaling pathways
Features of keratinopathies depend on ____
Features of keratinopathies depend on tissues in which mutated keratin gene is expressed
(pachyonychia congenita - nails soles, oral; monilethrix involves hair follicles; palmoplantar keratoderma involves mutations KRT9 and affects palsms and soles)
Epidermolysis bullosa simplex involves mutations in ___ or ___ that cause ___
Epidermolysis bullosa simplex involves mutations in KRT5 or KRT14 that cause an autosomal dominant blistering disorder with cleavage through the basal cells of epidermis where expressed
Junctional epidermolyis bullosa is caused by missing proteins that are interacting components of the ___ and function to bind epidermis to dermis
Junctional epidermolyis bullosa is caused by missing proteins that are interacting components of the hemidesmosomes and function to bind epidermis to dermis
(autosomal recessive, generalized blistering / early demise)
Dystrophic epidermolysis bullosa is caused by mutations in ____
Dystrophic epidermolysis bullosa is caused by mutations in collagen 7 gene
- Dominant dystrophic form: missense point mutations in 1 allele, blistering and scarring at sites of trauma
- Recessive dystrophic form: mutations on both alleles (effectively no collagen 7), severe generalized blistering of skin and mucosa, growth retardation, hypoalbuminemia, anemia, die of metastatic skin cancer if survive childhood
Tumor syndromes involve ___, are usually ___, and mutations usually lead to ___
Tumor syndromes involve loss of heterozygosity, are usually autosomal dominant, and mutations usually lead to insufficient inhibition of tumor oncogenes and activation of signaling pathways
- Loss of heterozygosity: 2nd mutation in previously normal allele, associated with tumor formation
Neurofibromatosis is caused by ____, leading to ____, and arises from ____
Neurofibromatosis is caused by deletions in neurofibromin (tumor suppressor gene), leading to Ras activation, and arises from loss of heterozygosity
- Pigmentary markers: multiple cafe-au-lait spots, Lisch nodules (eyes)
- Optic gliomas and plexiform neurofibroma are usually congenital but can grow and become malignant
- Dermal neurofibromas in adolescence and beyond
- Autosomal dominant
Basal cell nevus syndrome involves ____ in young children and ____ cancers and ____ tumors due to ____
Basal cell nevus syndrome involves medulloblastoma in young children and basal cell cancers and ovarian tumors due to loss of heterozygosity
- Autosomal dominant
- Developmental abnormalities
- Cysts of jaw and ski
Tuberous sclerosis is caused by mutations in ___ or ___, which ___
Tuberous sclerosis is caused by mutations in hamartin (TSC1) or tuberin (TSC2), which interact to inhibit mTOR signaling
- Multiple white spots
- Often early seizures, retardation
- Multiple different types of tumors
Exome includes 1% of genome but ___ of pathogenic mutations
Exome includes 1% of genome but 99% of pathogenic mutations
(genotyping is faster and less costly)
Understanding of genetics of genodermatoses can help patients by allowing ____ and ____
How understanding of genodermatoses can help patients by allowing prenatal diagnosis and pathogenesis-based protein and gene therapy
- Amniocentesis / chorionic villus sampling at end of 1st trimester allows action
- In vitro fertilization guarantee normal baby through implanatation of only normal fertilized eggs
- Add what is missing via recombinant protein
- Skip bad area of gene: aminoglycosides skip over exons w/ null mutations
- Fix cells via ex vivo gene therapy
- Stem cell transplant
- Induced pluripotent stem cells to correct cells and introduce as stem cells
- Gene knockdown to get rid of back protein
- CRISPR / Cas to clear and fix
- Blocking an activated signaling pathway: topical rapamycin for tuberous sclerosis, hedgehog inhibitors for BCNS
- Small molecules to target specific pro-inflammatory signaling pathway
___ gets rid of bad protein, while CRISPR / Cas ___ and ___
Gene knockdown gets rid of bad protein, while CRISPR / Cas clear and fix
____ for tuberous sclerosis and ____ for BCNS function by blocking an activated signaling pathway
Topical rapamycin for tuberous sclerosis and hedgehog inhibitors for BCNS function by blocking an activated signaling pathway
Ichthyoses have a strong ____ gene signature that most closely resembles ____
Ichthyoses have a strong Th17/IL-23 gene signature that most closely resembles psoriasis
