Ehlers Danlos Syndrome Sarah V. Kelly, M.D.

Case Presentation 52 year-old married female dentist with two adult children CC: chronic diarrhea PMH: Depression, generalized anxiety, “thyroid disease”, “fibromyalgia” and peri-menopause Medications: fluoxetine (prozac) and levothyroxine (synthroid) Allergies: NKDA Surgical history: None, 2 NSVDs with no complications

Case Presentation Intermittent diarrhea and constipation (IBS-like symptoms) Wonders if GI symptoms related to “something I’m eating” or an infection (possibly related to travel)? Denies fevers, chills or night sweats. No significant weight loss. c/o significant fatigue that has not improved with treatment of autoimmune thyroid disease (Hashimoto’s thyroiditis)

Review of Systems Expresses concern about increasing episodes of debilitating headaches and difficulty focusing at times Occasional palpitations, particularly when “standing up too quickly” Others have labeled her as a “hypochondriac” or implied that her symptoms are not “real” Recently diagnosed with fibromyalgia Notices similar symptoms in her daughter

What is it? “If you cannot connect the issues, think connective tissues” – Laura Bloom. https://www.youtube.com/watch?v=Gkorh94PTFg

EDS: What is it? A group of inherited disorders caused by qualitative and/or quantitative abnormalities in collagen production Collagen is present in nearly every tissue and organ system in the body EDS associated with many widespread complications and symptoms; tissues often involved are skin, joints, and blood vessel walls There are 6 major types that vary in their specific cause and presentation (dependent on the form of collagen affected) Recorded prevalence of 1 in 2,500 (often misdiagnosed) Most cases inherited in autosomal dominant pattern

Major Symptoms Stretchy, loose, and/or “velvety” skin Flexible joints with hypermobility (causes chronic joint pain, damage and reactive muscle pain) Abnormal wound healing Joint dislocations and/or partial dislocations (aka subluxations) Easy bruising Muscle pain and weakness Heart and vascular problems such as aneurysms, MVP, aortic root dilatation Organ rupture, hernia

Joint and Skin Findings

Associated Conditions Autoimmune thyroid disease Chronic pelvic pain from endometriosis and/or pelvic congestion syndrome Depression, generalized anxiety disorder and obsessive compulsive disorder Chiari malformation GI symptoms/IBS related to mast cell activation disorder (MCAD) and “leaky gut” Autonomic dysfunction from Postural Orthostatic Tachycardic Syndrome (POTS) Temporomandibular Joint Dysfunction (aka TMJ) Chronic (daily) headache Reduced responsiveness to anesthetics and opiate pain medication Clumsiness, falls, trauma, etc. due to decreased proprioception and strength

Natural History Childhood Young adulthood Diagnosis of EDS in children requires high suspicion EDS kids often have chronic, repetitive complaints of non- specific pain (“growing pains”, joint aching, headaches) and FATIGUE (? Depression) May have increased risk of fractures Young adulthood Relatively asymptomatic Hypermobility of childhood persists or progresses Adulthood = Restrictive phase of disease, degenerative arthritis predominates

Differential Diagnoses Fibromyalgia Lyme disease Seronegative arthritis Munchausen’s Syndrome, Conversion Disorder Marfan Syndrome Osteogenesis Imperfecta Other rare conditions: Loeys-Dietz Syndrome, Stickler Syndrome, Williams Syndrome, Aarskog-Scott Syndrome, Fragile X Syndrome, Achondroplasia, hypochondroplasia

Classical Type (Types I & II) Generalized hyperextensibility of joints and skin Easy bruising, hemarthroses Poor wound healing and retention of sutures Congenital dislocation of hips Scoliosis Mitral valve prolapse

EDS – Classic Type

Hypermobility Type (Type III) Most common type (reported in up to 1 in 5,000, probably MUCH higher) Exact cause unknown; no genetic test available Autosomal dominant inheritance Cardinal feature: Joint hyper-extensibility Chronic degenerative joint disease with advanced, premature osteoarthritis Less skin involvement Mitral valve prolapse

EDS - Hypermobility

EDS - Hypermobility

Vascular Type (Type IV) Most serious type (1 in 250,000) Prone to ruptured/dissected arteries and aneurysms, intestinal and uterine rupture Easy bruising Visible veins beneath thin, translucent skin Characteristic facies: protruding eyes, thin nose/lips, sunken cheeks, small chin Joint involvement variable Relative deficiency in type III collagen

EDS – Vascular Type

Kyphoscoliosis Type (Type VI) Arthrochalasia Type (Type VIIA/VIIB) Dermatosparaxis Type (Type VIIC)

Kyphoscoliosis Type

Diagnosis Family History/Pedigree Physical Exam/History Laboratory studies: rule out rheumatologic disease and assess disease status Genetic testing (PCR) for known disease- causing mutations (classical, vascular, kyphoscoliosis and arthrochalasis types) Others testing: skin biopsy, urine test (kyphoscoliosis type), prenatal and pre- implantation testing

Treatment No specific cure available Goal: Manage symptoms and prevent complications Important EDS screening: Echocardiogram DEXA scan CNS imaging (including vascular scans) Patient education and genetic counseling Rehabilitation and Maintenance – PT/OT, aquatic therapy Postural training and body awareness Chronic pain management Orthopedic surgery (in skilled hands)

Non-restorative Sleep Disease Cycle of EDS Joint pain & Fatigue Non-restorative Sleep Stress/Anxiety Depression Decreased mobility Disruption in Neurotransmitters Adrenal Fatigue & Hormonal Imbalances

Managing Hypermobility Goal: Prevention of disease progression and disability, restoration of normal form and function PT/OT – Strengthening muscles within a normal (reduced) range of motion Splinting when necessary for healing Avoidance of high impact activities or activities that promote hypermobility (dance, gymnastics, yoga, etc.)

What is helpful? Adhering to a healthy (paleo-like) LIFESTYLE Remaining mentally and physically active Getting enough….but not too much…rest Social support Cognitive behavioral therapy Mindful selection of supplements and medications Medical THC ?

References Klippel, John. Primer on the Rheumatic Diseases. Edition 12. Atlanta, GA: Arthritis Foundation; 2001: 584-586. www.utdol.com www.mayoclinic.com Ramanath VS, Oh JK, Sundt III TM, Eagle KA. Acute Aortic Syndromes and Thoracic Aortic Aneurysm. Mayo Clinic Proceedings. 2009; 84(5):465-479. Beighton P,  DePaepe A,  Steinmann B,  Tsipouras P  and  Wenstrup RJ.  Ehlers-Danlos Syndromes: Revised Nosology,  Villefranche, 1977.  Am J Med Gen 1998; 77: 31-37 http://www.ncbi.nlm.nih.gov

https://www.youtube.com/watch?v=HkYr_WY-TRA