Ehlers-Danlos Syndrome and Comorbid Conditions

Ehlers-Danlos Syndrome (EDS) is one of the most complex conditions affecting the human body because EDS impacts almost every system. This complexity arises primarily from the pervasive role of connective tissues, which provide structure and support to skin, blood vessels, organs, and joints. Additionally, other less-understood factors contribute to the syndrome's complexity. Although it has one name, EDS is not a solitary condition. Instead, it serves as a central node in a vast network of comorbid conditions, painting a picture of intricate medical relationships that demand attention. The condition is so multifaceted that entire books have been written about EDS, yet there is still more to learn. This article explores both the overlooked symptoms and the widely researched comorbidities of EDS.

Understanding Ehlers-Danlos Syndrome

EDS encompasses a group of disorders affecting connective tissue, leading to symptoms such as weakened tissues, increased risk of injury, and mobility issues. Each form of EDS has unique characteristics, but all share a common thread: the involvement of connective tissue abnormalities across multiple body systems.

The Concept of Comorbidities

In the context of EDS, comorbidities refer to the simultaneous presence of two or more disorders in a patient. These comorbid conditions span a wide range, from neurological and spine issues to digestive and cardiovascular disorders. The presence of these comorbidities complicates the clinical picture of EDS, necessitating a comprehensive and multidisciplinary approach to management and treatment.

Common EDS Comorbidities

Neurological and Spine Problems:

• Disc Degeneration: Accelerated degeneration occurs due to weakened connective tissues supporting the spine.
• Scoliosis (Spine Curvature): Scoliosis is common in EDS, scoliosis results from joint instability and abnormal connective tissue development.
• Craniocervical Instability: CCI is instability at the junction between the head and neck. CCI can cause headaches, dizziness, and neurological symptoms due to spinal cord compression.
• Chiari Malformation: Chiari malformation in EDS may be aggravated by connective tissue weakness in the skull.
• Migraines: Migraines in EDS are often linked to cervical instability, autonomic dysfunction, or vascular abnormalities.
• Syringomyelia: Fluid-filled cysts in the spinal cord are more common due to structural abnormalities in connective tissue.
• Intracranial Hypertension: Elevated cerebrospinal fluid pressure may stem from impaired vascular integrity.
• Tethered Cord Syndrome: This condition, more prevalent in EDS, results from abnormal spinal cord attachment causing pain and neurological issues.
• Dystonia: Dystonia is Involuntary muscle contractions. Dystonia may arise from neurological complications related to EDS.
• Tarlov Cysts: Fluid-filled sacs along the spinal cord are frequently asymptomatic but can cause pain in EDS due to nerve compression.

Joint Issues

• Chronic Joint Pain: Persistent pain occurs due to joint instability and repeated injuries.
• Frequent Dislocations: Weak connective tissues result in frequent subluxations and dislocations.
• Susceptibility to Osteoarthritis: Early-onset osteoarthritis is common due to chronic joint instability.
• Atlantoaxial Instability (AAI): Atlantoaxial Instability at the upper cervical spine can cause severe neurological symptoms.
• Slipping Rib Syndrome: Joint instability in the rib cage of some EDS patients can lead to slipping rib syndrome.
• There are a wide range of other orthopedic issues in EDS, and many more of them are detailed in this article: "20 Orthopedic Issues in Ehlers-Danlos Syndrome"

Digestive Disorders

• Acid Reflux: Weakness in the esophageal sphincter leads to increased gastroesophageal reflux in EDS.
• Irritable Bowel Syndrome (IBS): Dysmotility and connective tissue abnormalities in the gut contribute to IBS symptoms in EDS.
• Hiatal Hernia: Weakness in connective tissue supports increases the risk of hiatal hernias as well as other types of hernias in other areas of the body.
• Gut Dysmotility, including Dysphagia and Gastroparesis: In patients with EDS, these GI conditions may occur due to impaired smooth muscle function and connective tissue defects.

Cardiovascular Problems

• Mild Dilation of the Aortic Root: This condition can predispose individuals to life-threatening aortic dissection, especially in Vascular EDS.
• Postural Orthostatic Tachycardia Syndrome (POTS): Autonomic dysfunction is common in EDS, causing symptoms like dizziness and tachycardia.
• Mitral Valve Prolapse: Common in EDS, due to weakened connective tissue in the heart valves.
• Raynaud's Phenomenon: Raynaud's is frequently observed in patients with EDS, but it is not frequently diagnosed.
• Low Blood Pressure: Autonomic dysfunction in EDS often leads to hypotension.

Skin Issues

• Stretchiness: Stretchiness is a common skin feature in EDS due to defective collagen.
• Abnormal Scarring: Fragile connective tissue leads to wide, atrophic scars.
• Easy Bruising: Vascular fragility increases susceptibility to bruising.
• Stretch Marks at a Young Age: Skin elasticity abnormalities cause early striae formation.
• Slow Wound Healing: Reduced collagen integrity causes slower wound repair.

Bladder Disorders

• Interstitial Cystitis: Chronic bladder pain and urgency are linked to connective tissue abnormalities and interstitial cystitis.

Sexual and Pelvic Health

• Sexual dysfunction: Autonomic dysfunction and vascular issues may contribute to erectile problems and other types of sexual dysfunction in EDS.
• PCOS and Endometriosis: Both conditions are more prevalent in EDS, likely due to hormone-related tissue changes.
• Pelvic Floor Dysfunction: Connective tissue weakness can cause pelvic dysfunction, pain and other issues including rectal prolapse.
• Pelvic Congestion Syndrome (PCS): Pelvic Congestion is a chronic condition frequenly observed in EDS.
• Premenstrual Dysphoric Disorder: PMDD is a severe form of premenstrual syndrome (PMS) that seems to be more prevalent in people with EDS and MCAS.

Dental Issues

• Periodontitis: Weak connective tissue in the gums increases susceptibility to periodontal disease, especially in periodntal EDS.
• Dental Crowding: Abnormal jaw development leads to crowded teeth.

Psychological Conditions

• Anxiety Disorders: Chronic pain and autonomic dysfunction contribute to heightened anxiety in EDS.
• Depression: Physical limitations and chronic pain are key factors in the prevalence of depression.
• PTSD: Living with a chronic illness and medical trauma increases PTSD risk.
• Autism Spectrum Disorder (ASD): Individuals with EDS are at a significantly increased risk of ASD, potentially due to shared genetic or environmental factors.
• Bipolar Disorder: Bipolar disorder is more prevalent in EDS, potentially linked to autonomic dysfunction and chronic stress.
• Attention Deficit Hyperactivity Disorder (ADHD): ADHD is highly associated with hypermobility and EDS, reflecting overlapping neurodevelopmental pathways.

Immunological and Allergies

• Mast Cell Activation Syndrome (MCAS): MCAS is common in hEDS. Symptoms of MCAS in hEDS include flushing, anaphylaxis, and chronic urticaria due to abnormal mast cell activation.
• Primary Immunodeficiency (PI): Impaired immune responses may occur in a subset of EDS patients.

Eye Conditions

• Detached Retina: Weakened retinal connective tissue increases detachment risk.
• Brittle Cornea Syndrome (BCS): BCS is a rare subtype of EDS marked by corneal fragility and rupture risk.
• Blue Sclera: Thinned scleral collagen in some types of EDS gives the sclera a bluish hue.
• Vision Problems (e.g., floaters, blurred vision): These issues may arise due to structural abnormalities in connective tissue.

Chronic Fatigue Syndrome

• ME/CFS: Chronic Fatigue Syndrome in EDS is multifactorial, involving autonomic dysfunction, chronic pain, and mitochondrial issues.

Autonomic Dysregulation

• Dysautonomia, including POTS: Dysregulated autonomic function in EDS leads to symptoms like dizziness, fainting, and rapid heart rate.

Pain Disorders

• Small Fiber Neuropathy: SFN is neuropathic pain resulting from damage to small sensory fibers. SFN has been found in 78% of EDS cases.
• Fibromyalgia: Overlapping pain syndromes suggest shared mechanisms between Fibromyalgia and hypermobile EDS.
• Complex Regional Pain Syndrome (CRPS): Exaggerated pain responses like those seen in CRPS are more common in connective tissue disorders.

Sleep Disorders

• Sleep Apnea: Weak airway connective tissue predisposes individuals to sleep apnea.
• Sleep Disturbances: Sleep Apnea, Dysautonomia, and nocturia often reduce sleep quality for EDS patients.

Bone Disorders

• Osteoporosis: Reduced bone density is linked to abnormal collagen synthesis and mast cell activation.
• Kyphosis: Spinal deformities, such as kyphosis, are more prevalent due to weak structural support.

Underrepresented and Rare Comorbidities

Thyroid Disorders

• Hypothyroidism and hyperthyroidism are frequently reported in individuals with EDS, exacerbating fatigue and cardiovascular symptoms.

Gallbladder Problems

• Gallbladder dysmotility and gallstones may occur due to impaired connective tissue function in the biliary tract.

Secondary Polycythemia and Nemaline Myopathy

• Rare conditions like secondary polycythemia and nemaline myopathy are occasionally reported, reflecting complex multisystem involvement in EDS.

Heat Intolerance

• Heat intolerance in EDS is linked to autonomic dysfunction and poor temperature regulation.

Sjogren’s Syndrome

• Sjogren’s syndrome frequently overlaps with EDS, contributing to dryness symptoms and immune system complications.

Multiple Sclerosis (MS)

• Though rare, MS has been observed in some EDS patients, suggesting a possible shared inflammatory pathway.

Elevated Liver Enzymes

• Elevated liver enzymes in EDS may indicate systemic inflammation or medication side effects.

Spiky Leaky Syndrome

• Spiky-Leaky Syndrome (SLS) is an emerging clinical phenomenon that links intracranial hypertension, cerebrospinal fluid (CSF) leaks, and a range of symptoms seen in hypermobility syndromes.

Advances in EDS Research

Ongoing research continues to expand our understanding of EDS and its myriad comorbidities. This includes exploring genetic mechanisms, improving diagnostic tools, and identifying targeted treatments for associated conditions.

Management Strategies for EDS Comorbidities

Addressing EDS comorbidities requires a tailored and integrative treatment approach, involving:

• Pharmacological Interventions: Medications for pain, autonomic regulation, and immune modulation.
• Physical Therapy: Targeted exercises to improve joint stability and mobility.
• Lifestyle Modifications: Diet, hydration, and avoidance of triggers for conditions like POTS or MCAS.
• Multidisciplinary Care: Collaboration among specialists in neurology, cardiology, gastroenterology, and more.

Navigating the Complexities of EDS

Living with EDS and its associated comorbidities demands resilience, patient education, and supportive care networks. While the challenges are significant, advances in research and personalized care offer hope for improved outcomes and quality of life.

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Gagnon, H., Lunde, C. E., Wu, Z., Novais, E. N., Borsook, D., & Sieberg, C. B. (2023). Exploring Comorbidities in Adolescent and Young Adults with Hypermobile Ehlers-Danlos Syndrome with and without a Surgical History: A Preliminary Investigation. Children (Basel, Switzerland), 10(9), 1562. https://doi.org/10.3390/children10091562

Jessica D. Chuchin & Tisha J. Ornstein. (2024) Fear avoidance, fear of falling, and pain disability in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Disability and Rehabilitation 46:18, pages 4234-4245.

Song, B., Yeh, P., & Harrell, J. (2020). Systemic manifestations of Ehlers-Danlos syndrome. Proceedings (Baylor University. Medical Center), 34(1), 49–53. https://doi.org/10.1080/08998280.2020.1805714

Ashley A Darakjian, Mira Bhutani, DeLisa Fairweather, S Christian Kocsis, Jessica J Fliess, Sami Khatib, Gabe J Weigel, Elizabeth J McCabe, Varsini Balamurugan, Evan E Perona, Jessica M Gehin, Emily R Whelan, Angita Jain, Hanna Sledge, David O Hodge, Todd D Rozen, Francis A Farraye, Ozan Soyer, Joseph Cheung, Stephanie L Grach, David Shirey Jr., Shilpa Gajarawala, Bala Munipalli, Chrisandra L Shufelt, Dacre R T Knight, Katelyn A Bruno, Similarities and differences in self-reported symptoms and comorbidities between hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorders, Rheumatology Advances in Practice, Volume 8, Issue 4, 2024, rkae134, https://doi.org/10.1093/rap/rkae134