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The Final Stretch:Inherited Disorders of Connective

Tissue

Jonathan A. Dyer, MD Philip C. Anderson Chair

Professor of Dermatology and Child Health University of Missouri – Columbia

E-mail: DyerJA@health.missouri.edu

Jonathan A. Dyer, MD

DISCLOSURESInvestigator: Scioderm; Allergan

DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY

New Classification of

EDS

• Beyond Villefranche..

• EDS: – Joint hypermobility

– Skin hyperextensibility

– Tissue fragility

Am J Med Genet Part C Semin Med Genet 175C:8–26

New Classification of EDS

• Clinical classification– Molecular confirmation for definite diagnosis

• NGS – panel vs. WES/slice

• Major/Minor criteria for each subtype

• Second pathogenetic classification also created - evolving

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EDS - Classical• AD; COL5A1 or COL5A2 mutations

– >90%

• Incidence ~1:5,000

• PROM; premature birth

Am. J. Med. Genet. Part C (Seminars in Medical Genetics) 175C:27–39 (2017)

EDS- Classical• Major:

– (1) Significant skin hyperextensibility* and atrophic scarring

– (2) Generalized joint hypermobility*

• Minimal criteria suggestive for diagnosis of classical EDS

– Major criteria (1) + either:

– Major criteria (2)

– Or: three of the nine minor criteria

Minor:(1) Easy bruising

(2) Soft, doughy skin

(3) Skin fragility (traumatic splitting)

(4) Molluscoid pseudotumours

(5) Subcutaneous spheroids

(6) Hernia (history of)

(7) Epicanthal folds

(8) Complications of joint hypermobility (e.g., sprains, dislocation/subluxation, pain, pes planus)

(9) Family history- 1st deg; meeting clinical criteriaAm J Med Genet Part C Semin Med Genet 175C:8–26

• Gorlin’s sign– Touch nose with tongue– 10% of population

• Metenier’s sign– Eyelid extensibility

EDS - Classical

Hyperextensibility/ Hypermobility

• No real consensus on how to measure

• What is normal?

• Beighton scale – 5/9 (?7/9 in kids)

• Age cutoffs? – validity- >50 yo invalid– Exercise; ethnicity; gender

• Skin hyperextensibility– >1.5 cm distal

forearms, dorsal hands

– >3 cm neck, elbow, knees

» Remvig et al. 2009

EDS - Classical

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Beighton scaleClinical Normal Unilateral Bilateral

Touch floor with open palms and fullyextended knees

0 1

>10 degree knee hyperextension 0 1 2

>10 degree elbow hyperextension 0 1 2

>90 degree passive dorsiflexion of 5th

finger0 1 2

Passive flexion of thumb to forearm 0 1 2

Beighton scale EDS - Classical

• Atrophic scarring• Minor criteria:

– Easy bruising– Molluscoid pseudotumours

• Calcification and fibrosis of old hematomas

– Spheroids• Spherical hard SQ nodules on

forearms and shins that calcify

– Epicanthal folds

• “doughy” or velvety skin

• Other “tricks”:– Swallowing own

tongue

– Absence of labial and lingual frenula is marker of EDS

EDS - Classical

Lancet; 357(9267):1500-2 2001

Reverse Namaskar sign

Indian J Dermatol. 2010 Jan-Mar; 55(1): 86–91.

EDS- ClassicalAdditional features

• Premature aging

• Cerebral spinal fluid leak

• Mitral valve prolapse, tricuspid prolapse: use strict criteria

• Chronic pain with normal X-ray

• Pregnancy: postpartum hemorrhage and uterine prolapse

EDS – ClassicalManagement

• Avoid trauma when possible– Low impact sports - if any– Nonweight bearing exercise– Fall proof the home (or the

child)• Physical therapy• CV: Echo

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• Wound care: – Closely spaced, multilayered absorbable

subcutaneous stitches– Closely spaced cuticular stitches

• Leave in at least twice as long • Can use absorbable stitches for cuticular closure

– Aggressive steri-strips at closure and after SR– Pressure bandages to decrease hematoma risk– Aggressive infection control

EDS- ClassicalManagement

Vascular EDS• AD; COL3A

• Major criteria:– Arterial aneurysm; dissection; rupture

• mid-sized

– Intestinal rupture - sigmoid

– Uterine rupture• Pregnancy - 5% mortality

– Family history

– Carotid-cavernous sinus fistula

Am J Med Genet Part C Semin Med Genet 175C:40–47

Vascular EDS• Easy bruising

• Thin, translucent skin

• Limited joint hypermobility– Distal digits

• Acrogeria– Aged appearing extremities

• Hands; C-terminal muts

– Tendon/muscle rupture

Vascular EDS - vEDS• Cong. hip dislocation;

talipes; pneumothorax; early onset varicosity; gingival recession; keratoconus

• “triangular facies”– Lobeless ears

– Thin vermilion

– Micrognathia

– Narrow nose

– Prominent eyes

Vascular EDS

• Diagnostic tests:– DNA blood test for mutation, deletion/duplication

– Biochemical test for abnormal electrophoretic mobility of type III procollagen from cultured skin fibroblasts (Byers lab, Seattle)

vEDS -Management• ID causative variants in COL3A1 (rare COL1A1 Arg-Cys muts)

• Modulate life style - minimize injury, risk of vessel/organ rupture

• ID and create care team

• Plan for emergency care (“vascular EDS passport”) - diagnosis and management plan for use when traveling

• Centralize management at centers of excellence (experience) if feasible

• Maintain BP in normal range / treat hypertension aggressively

• Surveil vascular tree (Doppler US, CTA (low radiation), MRA - annual

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Hypermobile subtypehEDS

• Most common -?gene- ~AD

• Hypermobile joints (JHS)– Pain*

– Degenerative joint disease

• Female > male– unclear significance

• ?easy bruisingAm J Med Genet Part C Semin Med Genet 175C:48–69

Hypermobile subtype• New criteria

– Stricter; online• Rubber glove skin test

• Phases: – Hypermobile

– Pain-MS- fibromyalgia-like• Nociceptive pain; Neuropathic

• Fatigue

– StiffnessAm J Med Genet Part C Semin Med Genet 175C:48–69

Ehlers-Danlos Patient Support• The Ehlers-Danlos Society

– P.O. Box 87463Montgomery Village, MD 20886P: 410-670-7577

– E-mail: info@ehlers-danlos.com

• The Ehlers-Danlos Society –Europe

– Office 735-37 Ludgate HillLondon, EC4M 7JN UKP: +44 203 887 6132

– E-mail: info@ehlers-danlos.com

EDS- Kyphoscoliosis• AR; PLOD1 defect

– lysyl hydoxylase 1

• Congenital: scoliosis; hip dislocation; severe hypotonia

• Motor delay; Generalized lax joints

• Thin, translucent skin

• Spontaneous arterial rupture

• Scleral fragility; microcornea

• Osteopenia Pediatric Neurology (2014)

EDS - Dermatosparaxis

• AR; ADAMTS2; procollagen N proteinase– Can’t cleave

• Severe skin fragility

• Hernia: umbilical/inguinal

• Short; short fingers; puffy eyelids

EDS - Arthrochalasia• COL1A1/COL1A2 muts

– Skip exon 6

– Loss of procollagen N-proteinase cleavage site

• Congenital: severe joint hypermobility; multiple dislocations; bilateral hip dislocation

• Muscle hypotonia

• Dysmorphic facies Clin Genet. 2012 August ; 82(2): 121–130

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Marfan’s syndrome

• AD - Mutations in fibrillin-1– 1:5,000

– ~25% de novo

• Abnormal:• Bone

• Ocular

• Cardiovascular

• Pulmonary; Muscle; Dura

Marfan syndrome

• Long extremities– Dolichostenomelia

– Arachnodactyly

– Arm span > height (>1.05)

– Reduced upper:lower body segment ratio

• Scoliosis: >60%

• Pectus: excavatum/carinatum

Pectus carinatum Pectus excavatum Striae

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The Hand in Marfans• Steinberg sign

– Fold thumb into closed fist

– + if thumb tip extends past palmar edge of hand

• Walker-Murdoch sign– + if thumb and fifth finger

overlap when gripping wrist with opposite hand

• Arachnodactyly

Marfans syndromeHand

Marfan syndromeEye

• Subluxation of lens– Ectopia lentis

• Myopia

• Retinal detachment

• Glaucoma

• Early cataract

Marfan syndromeHeart

• Aortic root dilatation– Measured via Z

score - Echo

– Media of arteries affected

• Mitral valve prolapse

Nat. Rev. Cardiol. 2010.31

Marfan syndromeDiagnosing

Score calculator - National MarfanFoundation Web site

• Ghent nosology– Score > or = 7 is

significant

https://www.marfan.org/dx/score

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Marfan syndromeFacies*

• Dolichocephaly– Long narrow head

• Downward slanting palpebral fissures

• Enophthalmos– Recession of globe in orbit

• Retrognathia

• Malar hypoplasia *3/5 features = 1 point

Marfan syndrome

• Lumbosacral

• CT/MRI - No preferred method

Nat. Rev. Cardiol..2010.30

Dural ectasia Spontaneous pneumothorax

Marfan syndromeProtrusio Acetabulae

• AP pelvis Xray– Medial protrusion of

acetabulum >3mm beyond ilio-ischial line

Marfan syndromeHindfoot deformity

• Hindfoot valgus - 2– Forefoot abduction

– Lowering of midfoot

• Not just simple “flat feet” -1

Nat. Rev. Cardiol.2010.31

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Marfan syndromeTreatment

• Conflicting data in recent studies

• Some show no benefit with losartan

• No effect: dominant negative

• + Effect: haploinsufficiency

• Combining beta-blockers and losartan is considered the best treatment at present

Osteogenesis imperfecta• Type 1 collagen

• Type I most common - AD– Thin, translucent skin, atrophic

scars

– Fragile bones; frequent fractures

– Hearing loss in ~50%

– Blue sclera

• Type II – AD/AR - often lethal

• Type III – AR - severe deformity

Osteogenesis imperfecta• Type 1 collagen

• Type I most common - AD– Thin, translucent skin, atrophic

scars

– Fragile bones; frequent fractures

– Hearing loss in ~50%

– Blue sclera

• Type II – AD/AR - often lethal

• Type III – AR - severe deformity

Osteogenesis imperfecta• Type 1 collagen

• Type I most common - AD– Thin, translucent skin, atrophic

scars

– Fragile bones; frequent fractures

– Hearing loss in ~50%

– Blue sclera

• Type II – AD/AR - often lethal

• Type III – AR - severe deformity

Cutis laxa

• Pendulous, inelasticskin– Not fragile

• Aged appearance

• Abnormal elastic fibers

Cutis laxa• Heterogeneous

– AD-elastin; fibulin5

– AR-fibulin 5 and 4• Most common; severe

– XLR (occipital horn syndrome) –ATP7A

• Lax distal skin; Brittle hair

• Thin face; inverted lower eyelids; hooked/beaked nose

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ADCL

ARCL type 1b ARCL type 1a/c

ARCL type 3

Debre- type CL

Cutis laxa

• Emphysema

• Aortic aneurysm

• Pulmonary artery/valve stenosis

• Hernia

• GI diverticula

• Lax joints

• Low ceruloplasminand bilateral exostoses of occiput– Occipital horn

syndrome

Buschke-Ollendorf syndrome

• AD; OMIM#

• LEMD3 gene

• Skin:– Dermatofibrosis

lenticularis disseminata• Elastoma

• Collagenoma

• Bone: osteopoikilosisArch Dermatol. 2010;146(1):63-68

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Pseudoxanthoma elasticum (PXE)• AR - Incidence – 1:50,000-75,000

• Fragmentation and mineralization of elastic fibers

• Clinical:– Classic “plucked chicken” skin

• May be seen in children quite early (adolescence)

– Retinal abnormalities• Peau d’orange – early

• Angioid streaks

– Vascular abnormalities• Claudication

• Infarction

PXE is a “metabolic” disease• Caused by defects in ABCC6

– Transmembrane efflux transporter expressed in liver and kidney• Minimal to no expression in skin

• Does transport ATP – major pyrophosphate (PPi) source

– PPi suppresses mineralization

– Progressive

– Serum from patients does not prevent Ca/PO4 precipitation in culture

– Skin grafting studies• wt skin on ABCC6 null mice = PXE

• ABCC6 null skin on wt mice = Normal

PXE - Treatment?

• Abcc6 null mice fed 5 times the standard amount of magnesium did not develop typical mineralization – Replicated in vitro

• J Invest Dermatol. 2009 Jun;129(6):1388-94

• Overexpression of anti-mineralization protein fetuin-A also showed some temporary benefit in mouse model

Why does it matter?

• Not as rare a disease as one would think

• Implications for other conditions where ectopic mineralization/ connective tissue fragmentation occurs in setting of solid organ disease?

Thanks for your attention and attendance!

Thank you for attending!

Jonathan A. Dyer, MD Philip C. Anderson Chair

Professor of Dermatology and Child Health University of Missouri – Columbia

E-mail: DyerJA@health.missouri.edu

Please contact me should you have any questions.