Ehlers-Danlos Syndrome (EDS)

Robert Whittaker, SPTUniversity of North Dakota

Overview Genetic defects affecting biosynthesis & structure of collagen

type (autosomal recessive – AR, autosomal dominant – AD)2

Villefranche Criteria 6 subtypes: classic, hypermobility (HT), vascular, kyphoscoliotic, arthrochalasis, & dermatosporaxis

Emerging Forms: cardiac-valvular, vascular-like, musculocontractural, spondylocheirodysplastic, brittle cornea syndrome, EDS/OI overlap, tenascin x deficient, progeroid, parodontitis, fribronectin deficient4

Can lead to serious adult complications including subluxations, sprains & chronic joint pain difficult to treat, may lead to devastating physical, social & emotional disability

ICD-9-CM Code 756: Other congenital musculoskeletal anomalies (Pattern 4A, 4B, 4F, 4I, 5B, 5C)5

EDS Classic2

Skin hyperextensibility; widened atrophic scars; joint hypermobility Smooth, velvety skin; molluscoid pseudotumors (fleshy lesions

over pressure points); subcutaneous spheroids (small, hard cyst-like nodules); Complications of joint hypermobility; muscle hypotonia, motor delay; easy bruising; manifestations of tissue extensibility and fragility; surgical complications; (+) family history

AD – COL5A1, COL5A2, & COL5A3 genes (Type V collagen: pericellular collagen which is ubiquitous in the CT space6; widely distributed in skin, bone, tendon, cornea, placenta, & foetal membranes)

Ultrastructural electron microscopy examination of skin shows irregular & loosely packed collagen fibrils & presence of typical ‘cauliflower’ fibrils

EDS Vascular2 Thin, translucent skin (fragile & splits easy); arterial/intestinal/uterine fragility or rupture;

extensive bruising; characteristic facial appearance (worst type, tendency to rupture arteries & hollow organs, major vascular or intestinal complications) Acrogeria (old looking); hypermobility of small joints; tendon & muscle rupture; talipes

equinovarus; early-onset varicose veins; arteriovenous, carotid-cavernous sinus fistula; pneumothorax/pneumohemothorax; gingival recessions; (+) family history, sudden death in a close relative

AD – COL3A1 (Type III collagen: fetal skin, blood vessels, organs, skin where reticular fibers are located, also seen in initial stages of wound healing & scar formation6)

Aneurysm, dissection or rupture of medium sized abdominal vessels (carotid, subclavian, ulnar, popliteal, and tibial arteries - coronary rupture rare)

Prophylactic measure – catheterization & arteriography should be avoided, could be fatal (ultrasound & subtraction angiography preferred) Thorough investigation of platelet function & clotting if surgery required Pregnant women high risk obstetrical program (unclear for caesarean section vs. vaginal delivery

preference)

Celiprolol – Long acting β1 antagonist with partial β2 agonist properties decreased incidence of arterial rupture by 3x

Strenuous activity should be avoided with aortic regurgitation due weakness of aortic wall3

EDS Kyphoscoliotic2

Generalized JHM, congenital hypotonia; congenital & progressive scoliosis; scleral fragility & rupture of the ocular globeTissue fragility, including atrophic scars; easy

bruising; arterial rupture; marfanoid habitus; microcornea; osteopenia/porosis; (+) family history

Deficient activity of lysyl hydroxylase 1 (LH1)Dx: ↑LP/HP ratio crosslinks in urine, ↓LH1 activity in

cultured skin fibroblasts, presence of mutation of PLOD1 gene (AR)

Type I: skin, tendon, bone, ligaments, joint capsules, annulus fibrosus2

EDS Arthrochalasis2

Generalized JHM with recurrent subluxations; congenital bilateral hip dislocationsSkin hyperextensibility; tissue fragility, including

atrophic scars; easy bruising; hypotonia; kyphoscoliosis; osteopenia/porosis

AD – COL1A1 & COL1A2Type I: skin, tendon, bone, ligaments, joint

capsules, annulus fibrosus6

EDS Dermatosparaxis2

Severe skin fragility; sagging, redundant skinSoft, doughy skin texture; easy bruising;

premature rupture of fetal membranes; large hernias (umbilical, inguinal); blue sclera & edema of eyelids; short stature & fingers

AR – ADAMTS2Type I: skin, tendon, bone, ligaments, joint

capsules, annulus fibrosus2

EDS Hypermobility2

1/5000, >females4 , most common type Hyperextensible &/or smooth, velvety skin; generalized JHM

Recurring joint dislocations, chronic joint/limb pain, (+) family history AD?

Severe JHM with recurrent joint dislocation and chronic mod-severe pain (also muscle cramps, tendinitis, headache, & fatigue) – leads to physical, social, emotional disability (>RA and comparable to fibromyalgia)

Impaired proprioception, postural control & muscular strength contribute to instability

LE muscle weakness caused by intrinsic muscular dysfunction associated with muscle pain & fatigue rather than reduced muscle mass

EDS-HT Cutaneous Features4

Hyper extensible - stretched beyond normal limit & immediately returns to original state ≥1.5-2cm at dorsum of hand = hyperextensible Velvety & smooth skin – skin texture difficult in toddlers Can facilitate the development of striae rubrae/distensae/atrophicae

(stretch marks) Abdominal fascia reduced CT stiffness can cause formation of

hernias in conjunction with increased abdominal pressure.  Minor wound healing defects & capillary fragility – may present

as atrophic, nonpapyraceous scars Capillary fragility causes increased tendency and delayed

ecchymosis (bruising) Disturbed perspiration (diaphoresis/hypohidrosis)

EDS-HT Mucosal & Oropharyngeal Features4

Xerostomia, xeropthalmia, & vaginal dryness Hypohidrosis, with mucosal xerosis could be remote

consequence of autonomic dysregulation Gingival bleeding due to mucosal fragility (brushing

teeth?)Blue sclera likely caused by more visible uveal blood

vessels though thinner scleraLack of frenulum – Gorlin’s SignOropharyngeal dysphagia may impede feeding with

consequent excessive weight loss, exacerbation of fatigue, and failure to thrive in children

Orthopedic Features4

Congenital capsuloligmentous laxity – subluxations, sprains, & soft tissue lesions (i.e. bursitis, tendonitis, synovitis, tenosynovitis, & fasciitis) Precocious osteoarthrits, spondylosis, & lower bone mass are

potential degenerative complications – may delay repair of fractures1

Muscle contractions, growth & molding of skeleton likely more effective in a body with lax joints

Decreased proprioceptive functions and JHM likely contributors of dysfunctions1

C-spine instability of OA junction, intracranial hypotension due to CSF leaks, TMJ dysfunction – migraine w/ w/out aura, tension headache, combination, post traumatic headache, craniofacial pain1

10% dextrose prolotherapy for TMJ to reduce pressure induced pain

Beighton Scale for JHM4

Joint/finding Negative

Unilateral

Bilateral

Criteria

Passive DF of 5th finger >90°

0 1 2 Major Criteria• Score 4/9• Arthralgia for >3

months in >4 jointsPassive flexion of thumbs to forearm

0 1 2

Hyperextension of elbows >10°

0 1 2 Minor Criteria• Score 1-3• Arthralgia in 1-3 joints• Hx of joint

dislocations• Soft tissue lesions >3• Marfan like habitus• Skin striae, hyper-

extensibility, or scarring

• Eye signs, lid laxity• Hx of varicose veins,

hernia, visceral prolapse

Hyperextension of knees >10°

0 1 2

Forward flexion of the trunk with knees fully extended & palms resting on the floor

0 Present = 1

EDS-HT Neurological Features4

High rate of myopathic electrophysiologic findings combined with reduced sensation & muscle weakness, increased muscle echo intensity, & myopathic changes at biopsy

Chronic/recurrent pain & fatigue most common complaints Widespread & involve the musculoskeletal system, nervous system, &

internal organs Pain associated with regular analgesic use, JHM, previous surgery, &

related to functional impairment independently from fatigue1

Headache – migraine most common Impaired proprioception at various joints (proximal interphalangeal

and knee joints) Impairs balance & posture Delayed autonomous walking, tip-toe walking, lack of crawling,

clumsiness, and possibly dyspraxia in infancy

EDS-HT Cardiopulmonary Features4

Dysautonomia most clinically relevant – orthostatic intolerance, postural tachycardia syndrome most common formMild mitral, tricuspid, & aortic valve regurgitation

(25%), true mitral valve prolapse (6%)rate of asthmatic symptoms & atopy associated

with increased lung volumes, impaired gas exchange, & tendency of both the lower & upper airways to collapsePersistent childhood wheezing by causing airway

collapse through CT defect affecting airways structure

EDS-HT & Fatigue1

Fatigue – sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, muscle weakness, & painEDS-HT/JHM possibly affects a significant number

of CFS patients.OSA may be leading cause of sleep difficultness

(restless leg syndrome/periodic limb movements) Dysautonomia major factor (high analgesic use

amplifies) & malabsorption possible triggers to fatigue

EDS-HT Ocular Features4

Blepharacholasis, antimongoloid palpebral slant, & blue scleraMyopia, unilateral ptosis, & tilted optic disc less

common

EDS-HT Gastrointestinal Features4

Chronic constipation, hiatus hernia, Crohn’s disease, fecal incontinence, rectal evacuatory dysfunction, & functional GI disorder Gastroesophageal reflux (with/without hiatus hernia), chronic/recurrent

gastritis, symptoms of delayed gastric emptying, recurrent abdominal pain, constipation/diarrhea

Unexplained abdominal pain in up to 86% of cases – bloating, reflux, heartburns, N/V, diarrhea, and consipitaiton1

Reduced fixation to adjacent structures causing visceroptosis & hernias, gut hypotonia/hypomobility, structural anomalies (i.e. dolichocolon)

Poorly localized forms of “organic” pain, such as fibromyalgia, headache, and irritable bowel disease, possibly related to an abnormal and intense enhancement of pain generated from external and visceral stimuli by CNS mechanisms (central sensitization)1

EDS-HT Pelvic/Gynocologic Features4

Irregular menses, meno/metrorrhagias, & sever dysmenorrhea Fertility & pregnancy usually unaffected

Obstetric & anesthetic interventions in order to prevent life threatening/disabling complications

Anesthesia induced hypotension facilitated by dysautonomia, meningeal fragility complicating CFS hypotension in case of epidural anesthesia, proneness to pelvic prolapse after episiotomy, apparently increased rate of suture dehiscence & minor hemorrhages after surgery

Pelvis – multiple/severe prolapses in nulliparous women – pain/discomfort due to specific complications such as constipation and recurrent urinary infections, dyspareunia partly due to vaginal dryness common form of pelvic pain (endometriosis, pelvic ring instability, and coccygeal joint dysfunction, likely more common)1

Urinary stress incontinence, uterine prolapse, & fecal incontinence Prolapse - Cesarean should be considered when vaginal delivery without

episiotomy cannot be anticipated

EDS-HT Psychological Features4

Psychology – inadequate adaption to the physical and social consequences of the disease (anxiety, depression, and other features of CNS fatigue), sense of stigmatization and limitation of the possibility of self actualization in daily living and social life are likely generated and induce sensation of living “a restricted life” in the affected individuals1

Secondary to chronic pain & disability, ostracism, & avoidance of relationships

Cognitive Behavioral Therapy

Differential Diagnosis4

Ultrastructural & molecular findings, skin biopsy, vascular imaging, & molecular testing not part of diagnosis Molecular testing & extensive vascular imaging for other EDS

subtypes Overlapping Disorders

Mucocutaneous fragility, JHM, chronic musculoskeletal pain & fatigue Neurologic Disorders

MS, ALS, hereditary & acquired sensory-motor &/or autonomic polyneuropathies, & CFS

Other Hereditary Connective Tissue Disorders with JHM “Battered child” syndrome, bleeding disorders, various rheumatologic

conditions with chronic musculoskeletal pain, such as ankylosing spondylitis, RA, & fibromyalgia

Treatment Lifestyle! Most cost & time effective solution (education - avoid

exacerbating) Multidisciplinary approach (geneticist, rheumatologist, neurologist,

psychiatrist, PT/OT, urologist/gynecologist, orthopedist, cardiologist, pneumologist, gastroenterologist, other)

Drugs Low-mod pain: ibuprofen, naproxen, paracetamol (NSAIDs - stomach!) Topical lidocaine & local injection of anesthetic/steroids (limited success) Inefficacy – tramadol, COX2 inhibitor, pain modulator dugs (tricyclic

antidepressants & serotonin/norepinephrine receptor inhibitors, amytriptyline best choice for neuropathic pain), duloxetine Help with satellite symptoms such as depression/sleep/irritable bowel disease

with limited side effects Ascorbic acid for capillary fragility, cofactor of polyl & lysyl hydroxylase

enzymes for biogenesis of collagens, Vitamin D for osteopenia, melatonin for sleep, & other neutraceuticals

Treatment Continued Fatigue

Fludrocortisone/vasoconstrictors – contraindicated in pts. with systemic HTN (βblockers or clonidine may improve BP & HR, β blockers should be avoided in pts. with asthma; octreotide with marked postprandial tiredness; modafinil for managing chronic fatigue in orthostatic intolerance

Additional water intake (isotonic solutions), high salt (HTN), carnitine &/or coenzyme Q10

Surgical & Anesthetic Surgery not contraindicated, increased time for soft tissue repair may lead

to muscle deconditioning postsurgical recovery Mild soft tissue fragility and delayed wound healing (double waiting time

before suture removal) Intubation should be carefully performed due to TMJ and C-spine and

mucosal fragility Epidermal CSF hypotension from leakage

PT Implications Proprioceptive Exercises

Wobble board/rhythmic stabilization Muscle Strengthening

Mid-range – stability (low resistance, high reps), Modalities

Heat/cold – inspect skin (heat can increase extensibility) TENS – pain, NMES – joint position

Assistive Devices May stress UE, W/C decrease stress on LE, silver ring splints for digits,

collar/braces Swimming (cardiac volume!), gentle stretching, massage, prevention

(pads), education, lifestyle recommendations, energy conservation

Questions?

References1. Castori M, Morlino S, Celletti C, et al. Management of pain and fatigue in

the joint hypermobility syndrome (a.k.a. ehlers-danlos syndrome, hypermobility type): Principles and proposal for a multidisciplinary approach. American Journal of Medical Genetics Part A. 2012;158A(8):2055-2070. doi: 10.1002/ajmg.a.35483.

2. De Paepe A, Malfait F. The ehlers-danlos syndrome, a disorder with many faces. Clin Genet. 2012;82(1):1-11. doi: 10.1111/j.1399-0004.2012.01858.x.

3. Goodman CC, Fuller KS. Pathology: Implications for the physical therapist. SAUNDERS W B Company; 2009.

4. Castori M. Ehlers-danlos syndrome, hypermobility type: An underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN dermatology. 2012;2012.

5. Guide to physical therapy practice. 2nd ed. APTA; 2003.6. Jeno, S., Mohr, T. Connective Tissue, Department of PT UND School of

Medicine and Health Science