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Dermatology
Genetic Basis of Cutaneous Diseases
Built from Dermatology, 5th Edition
What’s inside
10 sections · 126 slides
Overview
- Overview of the genetic basis of skin disease
Introduction and classification
From gene discovery to a molecular map of skin disease
- Growth of genodermatosis gene discovery
- ~5000
- Why classify skin disease by molecular defect
- McKusick's Online Mendelian Inheritance in Man (OMIM)
Genotype-phenotype correlations
Why one gene can cause many diseases, and many genes one disease
- Five ways one gene's mutations can diverge
- Allelic heterogeneity: one gene, many diseases
- Domain-specific mutations change the phenotype
- Same gene, different inheritance pattern
- Opposite mutations, opposite diseases
- Mutation type sets disease severity
- Locus heterogeneity: many genes, one disease
- Griscelli syndrome: locus heterogeneity with distinct features
Molecular classification of skin disorders
Grouping genodermatoses by the broken protein or pathway
- Molecular classification of hereditary skin disorders
- Molecular classification of genetic skin disorders.
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Molecular classification of genetic skin disorders. (continued)
- Where to find detailed tables for each disease group
- Groups of monogenic skin disorders listed in tables elsewhere in the book.
- Groups of monogenic skin disorders listed in tables elsewhere in the book. (continued)
- Groups of monogenic skin disorders listed in tables elsewhere in the book. (continued)
Structural protein and adhesion defects
Keratins, desmosomes, gap junctions, and matrix adhesion
- Keratin gene defects and their skin diseases
- How keratin pairing explains locus and allelic heterogeneity
- Desmosomes hold skin cells together
- Desmoglein 4 loss causes recessive monilethrix
- Connexins and gap junctions link cell activity
- Connexin disease spectrum and lymphatic connexins
- Hemidesmosomes anchor skin to its basement membrane
- Kindler EB: the one adhesion disease from actin, not keratin
Transporters and the nuclear envelope
Membrane pumps, channels, and the nucleus's own scaffolding
- Transmembrane transporter defects in skin disease
- H syndrome: a nucleoside transporter defect
- Calcium pump defects: Darier and Hailey-Hailey disease
- What the calcium pump genes actually do
- ABC transporters: a shared family, many diseases
- Pseudoxanthoma elasticum: a transporter disease, not a matrix disease
- ABCA12 dose explains harlequin versus lamellar ichthyosis
- Nuclear envelope defects (laminopathies)
- Lamin genes and related nuclear proteins
Signaling pathway defects
Inflammation, tumor growth, RAS/MAPK, and WNT signaling gone wrong
- Pyrin/NOD family defects and autoinflammatory disease
- The autoinflammatory skin-disease spectrum
- Hereditary tumor syndromes: three broken-mechanism types
- Defective DNA repair (caretaker) genes
- Telomere maintenance and dyskeratosis congenita
- Defective tumor suppressor (gatekeeper) genes
- PTEN, PI3K/AKT, AMPK, and cyclic AMP signaling
- Activated oncogenes drive some hereditary tumors
- Hereditary skin disorders with benign skin tumors
- Selected hereditary skin disorders characterized by benign skin tumors.
- Selected hereditary skin disorders characterized by benign skin tumors. (continued)
- Selected hereditary skin disorders characterized by benign skin tumors. (continued)
- Selected hereditary skin disorders characterized by benign skin tumors. (continued)
- Hereditary skin disorders with skin cancer risk
- Selected hereditary disorders associated with skin cancer.
- Selected hereditary disorders associated with skin cancer. (continued)
- Hereditary skin disorders with extracutaneous cancer
- Selected hereditary skin disorders associated with extracutaneous cancer.
- Selected hereditary skin disorders associated with extracutaneous cancer. (continued)
- Selected hereditary skin disorders associated with extracutaneous cancer. (continued)
- Selected hereditary skin disorders associated with extracutaneous cancer. (continued)
- Selected hereditary skin disorders associated with extracutaneous cancer. (continued)
- Selected hereditary skin disorders associated with extracutaneous cancer. (continued)
- Selected hereditary skin disorders associated with extracutaneous cancer. (continued)
- Selected hereditary skin disorders associated with extracutaneous cancer. (continued)
- RASopathies: one pathway, two mutation directions
- RAS-mitogen-activated protein kinase (MAPK) signaling
- Shared features across RASopathies
- Costello syndrome: a distinct RASopathy
- Targeted therapy in the RAS-MAPK pathway
- WNT/beta-catenin signaling in the skin
- WNT/beta-catenin signaling pathway
- Goltz syndrome: a PORCN defect
- WNT10A, Gardner syndrome, and R-spondins
Contiguous gene syndromes and mosaicism
When a deletion spans several genes, or a mutation only reaches part of the body
- Contiguous gene syndromes
- More examples of contiguous gene syndromes
- What mosaicism means in skin disease
- Mosaic signaling mutations cause common birthmarks
- Type 1 versus type 2 mosaicism
- Confirmed examples of type 1 and type 2 mosaicism
- FGFR3 defects: germline versus mosaic mutation
- Type 2 segmental Hailey-Hailey disease
- X-inactivation creates 'functional mosaics'
- X-linked dominant, male-lethal disorders in female carriers
- Female carriers of X-linked hypohidrotic ectodermal dysplasia
- IFAP syndrome: ichthyosis, hair loss, light sensitivity
- Revertant mosaicism: the body's own gene correction
- How revertant mosaicism corrects a mutation
- Ichthyosis en confetti: revertant mosaicism in action
Chromosomal disorders
When a whole extra or missing chromosome changes the skin
- Aneuploidy: extra or missing chromosomes
- Skin findings associated with chromosomal aberrations.
- Skin findings associated with chromosomal aberrations. (continued)
- Skin findings associated with chromosomal aberrations. (continued)
- Down syndrome: skin and mucosal findings
- Phylloid hypomelanosis: mosaic trisomy 13
Insights, diagnosis, and treatment
What genodermatoses teach us about common disease, and how understanding leads to therapy
- Rare gene defects explain common autoimmune skin disease
- Wound healing and autoantibody discoveries from rare disease
- Interferonopathies inform lupus and dermatomyositis therapy
- Filaggrin, atopic dermatitis, and asthma
- SPINK5 and Netherton syndrome inform atopic dermatitis
- Prenatal diagnosis has moved from skin biopsy to DNA testing
- Modern prenatal and preimplantation testing options
- Gene therapy for epidermolysis bullosa
- In vivo gene therapy and gene editing for EB
- Targeting the mTOR pathway: sirolimus and everolimus
- More pathway-targeted therapies for genodermatoses
- Key takeaways
- References
- References (continued)
- References (continued)
- References (continued)
- References (continued)
- References (continued)
- References (continued)
- Dermatology, 5th Edition (2-Volume Set)