Ehlers- Danlos Syndrome (EDS)

1. Ehlers-Danlos Syndrome (EDS) Robert Whittaker, SPT University of North Dakota

2. Overview • Genetic defects affecting biosynthesis & structure of collagen type (autosomal recessive – AR, autosomal dominant – AD)2 • VillefrancheCriteria 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

3. EDS Classic2 • Skin hyperextensibility; widened atrophic scars; joint hypermobility • Smooth, velvety skin; molluscoidpseudotumors (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

4. 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; talipesequinovarus; 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

5. EDS Kyphoscoliotic2 • Generalized JHM, congenital hypotonia; congenital & progressive scoliosis; scleral fragility & rupture of the ocular globe • Tissue 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

6. EDS Arthrochalasis2 • Generalized JHM with recurrent subluxations; congenital bilateral hip dislocations • Skin hyperextensibility; tissue fragility, including atrophic scars; easy bruising; hypotonia; kyphoscoliosis; osteopenia/porosis • AD – COL1A1 & COL1A2 • Type I: skin, tendon, bone, ligaments, joint capsules, annulus fibrosus6

7. EDS Dermatosparaxis2 • Severe skin fragility; sagging, redundant skin • Soft, doughy skin texture; easy bruising; premature rupture of fetal membranes; large hernias (umbilical, inguinal); blue sclera & edema of eyelids; short stature & fingers • AR – ADAMTS2 • Type I: skin, tendon, bone, ligaments, joint capsules, annulus fibrosus2

8. 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

9. 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 striaerubrae/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)

10. 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 sclera • Lack of frenulum – Gorlin’s Sign • Oropharyngealdysphagia may impede feeding with consequent excessive weight loss, exacerbation of fatigue, and failure to thrive in children

11. Orthopedic Features4 • Congenital capsuloligmentouslaxity – 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-spineinstability 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

12. Beighton Scale for JHM4

13. EDS-HT Neurological Features4 • High rate of myopathicelectrophysiologic findings combined with reduced sensation & muscle weakness, increased muscle echo intensity, & myopathicchanges 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

14. EDS-HT Cardiopulmonary Features4 • Dysautonomia most clinically relevant – orthostatic intolerance, postural tachycardia syndrome most common form • Mild mitral, tricuspid, & aortic valve regurgitation (25%), true mitral valve prolapse (6%) • rate of asthmatic symptoms &atopyassociated with increased lung volumes, impaired gas exchange, & tendency of both the lower & upper airways to collapse • Persistent childhood wheezing by causing airway collapse through CT defect affecting airways structure

15. EDS-HT & Fatigue1 • Fatigue – sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, muscle weakness, & pain • EDS-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

16. EDS-HT Ocular Features4 • Blepharacholasis, antimongoloid palpebral slant, & blue sclera • Myopia, unilateral ptosis, & tilted optic disc less common

17. EDS-HT Gastrointestinal Features4 • Chronic constipation, hiatus hernia, Crohn’sdisease, fecal incontinence, rectal evacuatorydysfunction, & 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

18. 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

19. 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

20. 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 • Mucocutaneousfragility, 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

21. 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 boweldisease 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

22. 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

23. 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

24. Questions?

25. References • 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. • 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. • Goodman CC, Fuller KS. Pathology: Implications for the physical therapist. SAUNDERS W B Company; 2009. • Castori M. Ehlers-danlos syndrome, hypermobility type: An underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN dermatology. 2012;2012. • Guide to physical therapy practice. 2nd ed. APTA; 2003. • Jeno, S., Mohr, T. Connective Tissue, Department of PT UND School of Medicine and Health Science