Dermatologic Features and Issues Scott Walsh MD PhD FRCPC Sunnybrook Health Sciences Centre University of Toronto Peter Gilgan Centre November 2 and 3 2019 Disclosures No conflicts with Industry relevant to this talk ID: 803962
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Slide1
The ILC Foundation:Ehlers Danlos Complex Dermatologic Features and Issues
Scott Walsh MD PhD FRCPC
Sunnybrook Health Sciences Centre
University of Toronto
Peter
Gilgan
Centre
November 2 and 3, 2019
Slide2Disclosures:No conflicts with Industry relevant to this talk.
Slide3Ehlers Danlos Syndromes:Cardinal features of EDS:Hyper-extensibility of the skin.Hypermobility of the joints.Tissue fragility (skin, blood vessels).
Many different types of EDS.
Slide4Ehlers Danlos Syndromes:
Type
of EDS
Former System
Gene
Inheritance
Features
ClassicI and IICollagen V (alpha I and II)ADAtypical scarring and hypermobilityHypermobileIII?ADHypermobility and painVascularIVCollagen III (rare collagen I)ADArterial rupture and small joint hypermobilityKyphoscoliosisVILysyl hydroxylase(PLOD1)ARKyphoscoliosis, hypotonia and scarring, globe rupture.ArthrochalasiaVIIa, VIIbCollagen I (alpha I and II)ADCongenital hip dislocation, hypotonia, scarring, severe hypermobility.DermatosparaxisVIIcProcollagen N peptidase (ADAMTS2)ARExtreme skin fragility, progressive joint hypermobility, redundant skin.
Adapted from Beighton
et al.
1998.
Am. J. Med. Genet.
77: 31-7.
Slide5Ehlers Danlos Syndromes:
Byers and Murray, 2012.
Slide6Malfait
et al.
2017
. Am. J. Med. Genet. Part C
Semin
Med Genet
175C: 8-26.
Slide7Malfait
et al.
2017
. Am. J. Med. Genet. Part C
Semin
Med Genet
175C: 8-26.
Slide8Malfait
et al.
2017
. Am. J. Med. Genet. Part C
Semin
Med Genet
175C: 8-26.
Slide9Malfait
et al.
2017
. Am. J. Med. Genet. Part C
Semin
Med Genet
175C: 8-26.
Slide10Ehlers Danlos Syndromes:Genes affected:Fibrillar collagens.Enzymes that process fibrillar collagens.Proteins that interact with collagens.
Slide11Ehlers Danlos Syndromes:Mechanisms:Not enough of the collagen.HaploinsufficiencyOne bad thread that makes the entire rope bad.
Dominant negative effect
Collagen that is weaker than normal and falls apart easily.
Abnormal solubility and strength
Slide12Outline:
Review structure of skin with respect to EDS and the interplay of different molecules:
Collagen
Elastin
Ground Substance
The role of Electron microscopy in inherited disorders of connective tissue.
Hypermobility Spectrum Disorder and changes that can occur with an altered matrix.
Effects on activity of other cell typesEffects on migration of other cells
Slide13Ehlers Danlos SyndromesSkin:CollagenStrength of skinElastinResiliency of skin
Ground Substance (proteoglycans and glycosaminoglycans)
Turgor or texture of skin
Abnormality in any one component can affect the proper assembly of the other components.
Slide14Ehlers Danlos Syndromes:Disorders primarily of disturbed collagen production (fibrillogenesis).The morphology and strength of collagen is compromised.
Slide15Ehlers Danlos SyndromesCollagen is the major protein in skin, ligament, tendon, bone.29 different types of collagen (43 genes).Triple helix (three threads wrapped around each other to make a tight rope).
Homotrimers (proteins from same gene)
Heterotrimers (proteins from different genes)
Slide16Ehlers Danlos Syndromes"velvety texture""doughy texture""thin skin""hyperextensible"Volar forearm - snap back.
Slide17Collagen:Most abundant protein in the body.70% of dry weight of dermis.
Collagen Definition:
Have areas where there is a right handed triple-helical domain consisting of 3 left-handed polypeptide chains with a Gly-X-Y sequence where X is often proline and Y is often hydroxyproline.
Small amino acids where the three threads come together and larger amino acids on the outside of the rope that can interact with other molecules.
Structural component of the extracellular matrix.
Slide18Collagen - ClassificationTwo broad classes:Fibrillar collagensform cross-striated fibrils with 67 nm periodicity.
Non-fibrillar collagens
do not form cross-striated fibrils as usually have non-collagenous portions (twists in the rope) that give molecule flexibility (arms for molecules to bind to).
Several of these different types of collagens interact to make a large collagen fibre in the skin.
Slide19Fang et al. 2012
Slide20Fang et al. 2012
Collagen V
Slide21Fang et al. 2012
Collagen V
Collagen I
Slide22Fang et al. 2012
Collagen V
Collagen I
Collagen III
Slide23Fang et al. 2012
Collagen V
Collagen I
Collagen III
FACIT Collagens
XII and XIV
Slide24Fibrillar Collagen - V5% of dermal collagen.Located at core of collagen fibrils in the skin.
Slide25Slide26Slide27Slide28Slide29Castori. 2012.
ISBN Dermatol.
751768.
Slide30Morais
et al.
2013.
Acta Dermatovenerol. Croat.
21: 118-22.
Slide31EDS-I/II – Classical typeADClinical:
Thinned/atrophic scars
Papyraceus, cigarette paper, fish mouth.
Molluscoid pseudotumours, spherules.
Hyperextensible skin
Joint laxity/hypermobility
Small and large joint.
COL5A1 or COL5A2 mutations.Morais et al. 2013. Acta. Dermatovenerol. Croat. 21: 118-22; Malfait et al. 2010. Genet. Med. 12: 597-605; Malfait et al. 2005. Hum. Mutat. 25: 28-37.
Slide32Fibrillar Collagen - IIIEmbryonic/fetal life.
10% of collagen in adult dermis.
Enriched in blood vessels, viscera (GI).
Homotrimer; larger than collagen I.
Forms a scaffold on which organs and blood vessels are built upon
.
Slide33Slide34EDS-IV – Vascular/ecchymoticAD with 2 clinical presentations:
Acrogeric variety
Mutations in triple helix or carboxy-end.
Characteristic facies
Non-acrogeric
Mutations in amino terminus or single null allele.
Clinical:
Thin, translucent skinArterial rupture/dissection/aneurysm/bowel perforation/uterine ruptureExtensive bruising+/- acrogeriahypermobility of small jointsVaricositiesfamily history of sudden death.Rx: ?aortic root graft; avoid NSAIDs, contact sports.25% one event by 20 years; 80% one event by 40 years.Oderich et al. 2004. J. Vasc. Surg. 42: 98-106; Germain and Herrera-Guzman, 2004. Ann. Genetic. 47: 1-9; Germain 2001. Ann. Vasc. Surg. 16: 391-7
Slide35Fibrillar Collagen IMost abundant collagen.80% of collagen in dermis; bone.
Two threads from one gene wrapped with one thread from a second gene.
Col1A1 and Col1A2/
Heterotrimer of [
ά
1(I)]
2
ά2(I).Best studied and model for fibrillar collagen biosynthesis.
Slide36Slide37Osteogenesis imperfecta
Slide38Fibrillar Collagen I
Condition
Arthrochalasia
EDS (Col 1A1 or 1A2)
Cardiac valvular EDS (1A2)
Classical EDS (1A1) - rare variants
Vascular EDS (1A1) - rare variant
Osteogenesis imperfecta - helical mutations (1A1 and 1A2)Caffey disease (1A1)OI/EDS overlap (1A2)Lu et al. 2019. Intractable and Rare Diseases Research. 8(2): 98-107.
Slide39Collagen Biosynthesis/Fibrillogenesis:Model Collagen ICollagen III (fetal)Collagen V (regulatory)
Many forms of EDS occur when there is a problem in formation of fibrillar collagen.
Slide40Biosynthesis of Fibrillar Collagen IFormed as a procollagen that becomes an insoluble mature collagen with processing.Transcription:
Upregulated by retinoic acid, TGF-B, insulin, ascorbic acid.
Down-regulated by glucocorticoids, FGF, TNF.
Slide41Biosynthesis of Fibrillar Collagen IWithin the cellEndoplasmic Reticulum:
Translation of mRNA into ER.
Emerging polypeptide is bound by:
HSP47 prevents aggregation in ER.
Prolyl-4-hydrolase and protein disulfide isomerase.
Peptidyl prolyl
cis-trans
isomerase.Post-translational enzymatic modifications occur while translation is being completed.
Slide42Dordoni
et al.
2016.
Am. J. Med. Genet.
170A: 2031-8.
Slide43Dordoni
et al.
2016.
Am. J. Med. Genet.
170A: 2031-8.
FKBP14-Related Ehlers Danlos Syndrome
Slide44FKBP14-Related EDS:ARPeptidyl-prolyl cis-trans isomerases.Features:KyphoscoliosisMyopathy
Joint hypermobility
Congenital hearing loss
Atypical scarring and skin redundancy.
Dordoni
et al.
2016.
Am. J. Med. Genet. 170A: 2031-8.
Slide45Biosynthesis of Fibrillar Collagen I5 Enzymes in ER:
Proly-4-hydrolase
Converts proline in Y of Gly-X-Y to hydroxyproline.
Cofactors Fe
+2
, O
2
, ascorbic acid, ά-ketoglutarate.Prolyl-3-hydrolaseConverts proline in X of Gly-X-Y to HYP when Y is already HYP.Cofactors Fe+2, O2, ascorbic acid, ά-ketoglutarate.Lysyl hydrolaseHydroxylates lysine residues in Y of Gly-X-Y.Cofactors Fe+2, O2, ascorbic acid, ά-ketoglutarate.Important for future glycosylation and cross-linking.Galatosyl-transferaseTransfers UDP-galactose to hydroxylysine.Collagen glycosyl-transferaseTransfers UDP-glucose to galactosyl hydroxylysine.
Slide46Overmans et al. 2010
Slide47Overmans et al. 2010
Ehlers Danlos Kyphoscoliotic type
Slide48EDS – Kyphoscoliotic (VIA)AR
Deficiency of lysyl hydrolase type I (PLOD).
Unable to tighten the final collagen molecule.
hydroxylate lysines and hence can’t later cross-link them for collagen stability and insolubility.
Clinical:
Kyphoscoliosis at birth
Scleral fragility with globe rupture/retinal detachment
Severe muscular hypotonia at birthGeneralized joint laxity+/- large artery rupture, atrophic scars, tissue fragility, marfanoid habitus, easy bruising, microcornea, osteopenia/osteoporosisTosun et al. 2014. Pediatr. Neurol. 51:566-9; Overmans et al. 2010. Am. J. Med. Genet. 149A: 2311-16.
Slide49Biosynthesis of Fibrillar Collagen IModified triple helix zippered up in ER.
Secretion of Procollagen
Aggregate laterally in golgi (loss of HSP47)
Secreted via golgi vacuoles along microtubules.
Secreted into crypts around cell (fibripositors).
Slide50Koide and Nagata, 2005.
Slide51Koide and Nagata, 2005.
Slide52Koide and Nagata, 2005.
Slide53Koide and Nagata, 2005.
Slide54Koide and Nagata, 2005.
Slide55Koide and Nagata, 2005.
Slide56Koide and Nagata, 2005.
Slide57Biosynthesis of Fibrillar Collagen IExtracellular Processing:Procollagen N-proteinase (ADAMTS2)
Clips one end to make the rope even.
Procollagen C-proteinase (BMP 1).
Clips the other end to make the rope even on the other end.
Lysyl
oxidase
Tightens the rope
Deaminates lysyl and hydroxylysyl residues (Cu).Allysyne or hydroxyallysine crosslinks.Now strong and insoluble collagen.
Slide58Malfait et al. 2004
Slide59Malfait et al. 2004
Dermatosparaxis
Slide60EDS- Dermatosparaxis type (VIIC)AR – due to deficiency of procollagen I N-proteinase.
With the rope frayed at one end, it breaks easily.
Clinical:
Severe skin fragility with avulsions
Sagging, redundant skin (cutis laxa)
+/- easy bruising, blue sclerae, PROM, joint laxity, umbilical hernias
Van Damme
et al. 2016. Genet. Med. 18: 882-91; Malfait et al. 2004. Am. J. Med. Genet. 131A: 18-28.
Slide61Hatamochi et al. 2014
Slide62Hatamochi et al. 2014
Arthrochalasia (VIIA/B)
Slide63EDS-Arthrochalasia type (VIIA/B)AD – missing the marker of where to cut the rope, and so the end stays frayed.
exon 6 (N-propeptide cleavage site) in either COL1
ά
(I) or COL1
ά
(II) genes.
Clinical:
Bilateral congenital hip dislocationsGeneralized and severe joint laxity+/- skin hyperextensibility, tissue fragility, atrophic scars, easy bruising, muscular hypotonia, wormian bones. N-propeptide remains associated and increases solubility of collagen and ↓feedback ↑collagen.Hatamochi et al. 2014. Gene 538: 199-203; Klaassens et al. 2011. Clin. Genet. 82: 121-30.
Slide64Collagen BiosynthesisType V Collagen regulates fibrillogenesis.Type 5 at nucleus of fibre with binding sites pointing outwards, surrounded by types I and III with FACIT collagens XII and XIV to link to outside.
Link to ground substance proteins, cell surface receptors and elastin.
Slide65The DermisCollagen - gives strengthElastin - gives resilienceGround substance - gives texture.
Slide66Elastin:Continuous network from the epidermal junction to the hypodermis.Gives skin its resilience.
Graduated amounts of mature elastin deposited on microfibrillar proteins.
Effect on collagen regulation.
Defects:
Marfan's Syndrome, Cutis laxa, Menkes.
Slide67Ground SubstanceAmorphous material of the extra-cellular and extra-fibrillar matrix.Binds water and maintains hydration of the dermis (texture).
Composed of polysaccharides with negative charges.
Glycosaminoglycans
Proteoglycans (protein core with glycosaminoglycan)
Proteins
Many associate with collagens and can regulate the diameter of collagen fibrils.
Slide68Schaefer and Schaefer, 2010
Slide69Castori
C.
et al.
2019.
Am. J. Med. Genet.
179A: 317-21
Slide70Musculocontractural EDS
Enzyme carbohydrate sulfotransferase 14 (CHST14) not working properly and one of the proteoglycans,
decorin
, doesn't get its proper
glycanation
and hence doesn't bind collagen properly.
Myopathy with muscle contractures.
Skin hyperextensibilitySkin fragilitySpinal deformities.
Slide71Musculocontractural EDS
Hirose T
et al.
2019.
BBA
. 623-31.
-linear bridges of proteoglycans rather than curved bridges.
-failure to regulate collagen fibre diameter and spacing.
Slide72Musculocontractural EDS
Hirose T
et al.
2019.
BBA
. 623-31.
-linear bridges of proteoglycans rather than curved bridges.
-failure to regulate collagen fibre diameter and spacing.
Slide73Musculocontractural EDS
Hirose T
et al.
2019.
BBA
. 623-31.
-linear bridges of proteoglycans rather than curved bridges.
-failure to regulate collagen fibre diameter and spacing.
Slide74Syx
D.
et al.
2019.
Human Mol. Gen.
28(11): 1853-64.
Slide75AEBP1-Related Classical-Like EDS:
New AR variant recently described.
Aortic carboxypeptidase-like protein in the ground substance that appears to be important in binding collagen fibres in skin, blood vessels, lung and bone (periosteum).
Hyperextensible skin
Joint hypermobility
Atrophic scars
Thin and translucent skin
OsteoporosisRitelli M. et al. Genes. 10 (135): 1-14; Syx D. et al. 2019. Human Mol. Gen. 28(11): 1853-64.
Slide76AEBP1-Related Classical-Like EDS:
Syx
D.
et al.
2019.
Human Mol. Gen.
28(11): 1853-64.
Slide77AEBP1-Related Classical-Like EDS:
Syx
D.
et al.
2019.
Human Mol. Gen.
28(11): 1853-64.
Slide78Ehlers Danlos Syndromes:
Genes affected:
Fibrillar and non-fibrillar collagens.
Enzymes that process fibrillar collagens.
Glycosaminoglycan synthesis (interacts with collagen to regulate diameter).
Matrix proteins that influence collagen diameter.
Slide79Role of Electron Microscopy:Normally collagen synthesis is tightly controlled with near identical size and spacing of molecules.Inherited disorders of connective tissue (IDCT) demonstrate variation in collagen size and interfibrillar spacing when assessed by TEM.Can be used to support the presence of an IDCT.
Slide80Ehlers Danlos Syndromes:Skin biopsy taken from upper inner arm or lower back/upper buttock (sun protected site).Glutaraldehyde and fixed for TEM.Magnification up to 500 000X.Can assess variations in collagen fibrils.
Slide81Mao and Bristow, 2001.
J. Clin. Invest.
107: 1063-9.
Slide82Hausser and Anton-Lamprecht, 1994.
Hum. Genet.
3: 394-407.
Classic EDS
Slide83Hausser and Anton-Lamprecht, 1994.
Hum. Genet.
3: 394-407.
Slide84Sobey, 2015.
Arch. Dis. Child.
100: 57-61.
Vascular type EDS
Slide85Dermatosparaxis
Van Damme
et
al. 2016.
Genet.
Med. 18: 882-91; Malfait
et al.
2004. Am. J. Med. Genet. 131A: 18-28.
Slide86Hermanns-Le and Pierard, 2007.
Am. J. Dermatopathol.
29: 370-3.
Hypermobile type EDS
Slide87Hermanns-Le
et
al. 2012.
J. Biomed. Biotech.
878107; Hermanns-Le and Pierard, 2007.
Am. J. Dermatopathol.
29: 370-3.
Hypermobile type EDS
Slide88Electron Microscopy and Collagen:EDS variants.Other inherited disorders of connective tissue:Osteogenesis imperfectaCaffey Disease
Marfan's
Syndrome
Loeys
-Dietz
Pseudoxanthoma elasticum
Cutis
laxaMenkes Acquired disorders:Scleredema, scleromyxedema, nephrogenic fibrosing dermopathy.
Slide89Slide90Slide91Slide92Hypermobility Spectrum Disorder:Likely many disorders with common presentation.AD.Previously EDS Hypermobile type (subtype now only classified as EDS Hypermobile type).Features:
Generalized joint hypermobility.
Chronic joint and muscular pain.
Recurrent joint dislocations or subluxations.
Symptoms of autonomic dysfunction (dysautonomia).
Easy bruising.
No widened/papyraceous scars.
Functional gastrointestinal disorders.Small fibre neuropathyMast cell disorders (from flushing and itch to mast cell activation syndrome)Behaves like an inflammatory disorder in many patients.Martin A. 2019. Eur. J. Med. Genet. In press; Forghani I. 2019. Balkan Med. J. 36: 12-6; Caston M. and Hakim A. 2017. Curr. Opin. Pediatr. 29(6): 640-9.
Slide93Hypermobile type EDS:No single gene to date:Proteoglycans that regulate collagens.FACIT collagens.Elastin-related proteins.
Slide94Molecular Basis of HSD?
Both HSD and
hEDS
fibroblasts in contrast to both controls and other types of EDS show the exact same:
Upregulation of specific wound receptors
Upregulation or inflammatory mediators
Disarray of extracellular matrix
Prevalence of myofibroblast transition from fibroblasts (seen in chronic wound responses) not seen in other types of EDS.Zoppi N. et al. 2018. BBA. 1010-1023.
Slide95Molecular Basis of HSD
Other Roles of a "Normal Matrix":
Migration and maturation of other
matrical
components (nerves, blood vessels, muscle, etc.)
Stabilization and activation of other cell types.
Mast cells are intimate matrix cells in skin and gastrointestinal tract. Is there an abnormal effect from the matrix?
Nerves are intimate with the matrix and could these be affected by the upregulated wound signals?
Slide96EDS Management from Dermatologic Perspective:
Slide97EDS - Management:Supplemental Vitamin C.Supplemental Vitamin A.Avoid glucocorticoids where possible.Protection from Trauma.
Avoid contact sports.
Avoid ASA.
Vasopressin or transexaminic acid.
Sobey, 2015.
Arch. Dis. Child.
100: 57-61; Morais
et al. 2013. Acta Dermatovenerol. Croat. 21: 118-22; Malfait et al. 2010. Genet. Med. 12: 597-605; Mantle et al. 2005. Med. Hypoth. 64: 279-83.
Slide98EDS - Management:Suturing woundsDouble layer closures.Stitches held twice as long.Additional tape bandaging over wounds.
Mast cell stabilization
Cromolyn, ketotifen,
monteleukast
, omalizumab
Antihistamines
Sobey, 2015.
Arch. Dis. Child. 100: 57-61; Morais et al. 2013. Acta Dermatovenerol. Croat. 21: 118-22; Mantle et al. 2005. Med. Hypoth. 64: 279-83;
Slide99Summary:
The skin matrix is a well-controlled interplay between:
Collagen
Elastin
Ground Substance
Electron microscopy can detect abnormalities in
matrical
structure and support a diagnosis of an inherited disorders of connective tissue.Hypermobility Spectrum Disorder has changes in the matrix that likely can exert effect on both the migration and subsequent activity of other cell types.