Ehlers-Danlos Syndrome & the Zebras

“When you hear the sound of hooves, think horses, not zebras.”

This is what medical students are taught.

In the medical field, the term "zebra" is used to describe rare diseases or conditions. To avoid misdiagnosing patients with rare illnesses, doctors are trained to assume that the simplest explanation is usually correct. However, this makes it more difficult for those with rare conditions to receive a diagnosis and treatment. Even more so because medical students are not being taught (enough) about rare diseases.

Ehlers-Danlos Syndromes are generally considered rarer genetic diseases, so those who live with EDS are referred to as medical zebras, though information gained over the last few years has shown that Hypermobile Ehlers-Danlos Syndrome is more common than once thought. The saying "not so much rare as rarely diagnosed" is being used more these days.

"What is Ehlers-Danlos Syndrome?"

Ehlers-Danlos Syndrome is a group of 13 inherited disorders that affect the formation and function of your connective tissues, primarily your skin, joints, and blood vessel walls. It affects virtually every organ system.

Connective tissue is a complex mixture of proteins, such as collagen, and other substances that provide strength and elasticity to the underlying structures in your body. It affects virtually every organ system, which can result in significant morbidity and mortality. Severe complications of this disease can include arterial rupture and organ rupture, though these complications are typically only seen in Vascular Ehlers-Danlos Syndrome (vEDS).

Some EDS features are seen across all types of Ehlers-Danlos Syndrome, including joint hypermobility, tissue fragility, widespread chronic pain, and gastrointestinal diseases. The current classification includes 13 types of Ehlers-Danlos Syndrome, and each type has its own genetic causes. This results in a unique set of features for each type of EDS.

"What are connective tissue and collagen?"

Understanding Collagen: Structure, Function, and Importance

Collagen is the most abundant protein in the human body, accounting for about 30% of the body's total protein. It serves as the primary building block of the body's skin, muscles, bones, tendons, ligaments, and other connective tissues. Additionally, collagen is found in organs, blood vessels, and the intestinal lining.

Proteins, including collagen, are composed of amino acids. The main amino acids that form collagen are proline, glycine, and hydroxyproline. These amino acids group together to form protein fibrils in a triple helix structure. For the body to create this triple helix, it also requires adequate amounts of vitamin C, zinc, copper, and manganese.

The primary role of collagen is to provide structure, strength, and support throughout the body. Specifically, collagen helps fibroblasts form in the dermis (the middle skin layer), which promotes the growth of new cells. It also plays a role in replacing dead skin cells, providing a protective covering for organs, and giving skin its structure, strength, and elasticity. Furthermore, collagen aids in blood clotting.

https://www.youtube.com/watch?v=w2BIlqVqSgc

Connective tissue, found throughout the body, offers support, protection, and structure to various body parts. Disorders related to connective tissue arise when these tissues cannot function properly. Collagen, as the primary component of connective tissue, is crucial for maintaining its integrity. Different types of collagen serve different functions, and genetic changes affecting collagen and related proteins can lead to conditions such as the Ehlers-Danlos syndromes. These syndromes result from alterations in genes that impact the structure and function of collagen and related connective tissue proteins.

"How common is Ehlers-Danlos Syndrome?"

The prevalence of Ehlers-Danlos syndrome (EDS) varies significantly depending on the subtype. Overall, EDS is estimated to affect approximately 1 in 5,000 people, but this figure may be an underestimation due to underdiagnosis, particularly with milder symptoms-- patients may not seek medical care. The hypermobility type of EDS (hEDS) is the most common subtype, with recent studies suggesting it affects about 1 in 500 to 1 in 5,000 individuals. This is a significant revision from earlier estimates, which were lower due to less awareness and less refined diagnostic criteria.

Classical EDS (cEDS) affects approximately 1 in 20,000 to 1 in 40,000 people and presents with skin hyperextensibility and joint hypermobility. Vascular EDS (vEDS) is rarer, affecting between 1 in 100,000 and 1 in 200,000 individuals, and is associated with serious complications such as arterial or organ rupture. Other subtypes, like dermatosparaxis and kyphoscoliotic EDS, are exceedingly rare, with fewer than 1 in a million cases documented globally.

The accurate prevalence of different EDS subtypes remains uncertain, as much of the available epidemiological data is based on older classification systems where genetic etiology was not a primary diagnostic criterion. However, increased awareness and improved diagnostic criteria, particularly for hEDS, suggest that prior estimates might have been low.

"What are the signs you may have EDS?"

Key Symptoms of EDS

One of the hallmark symptoms of EDS is joint hypermobility, where joints are loose and unstable, frequently dislocating or subluxating, resulting in (varying degrees of) chronic pain. Skin manifestations are also common, with the skin being extremely soft, velvety, and/or stretchy, bruising easily, and healing poorly, leading to atrophic scarring. Individuals with EDS often experience (extreme) musculoskeletal pain that is chronic and widespread, affecting both joints and muscles. Alongside all of that, (debilitating) Fatigue is a common symptom.

Tissue fragility in Ehlers-Danlos Syndrome (EDS) is a hallmark feature resulting from defective collagen, which leads to weakened connective tissues that are easily damaged. This manifests in several ways, including:

• Severe Skin Fragility: Characterized by easy tearing, poor wound healing, and the presence of atrophic scars.

• Bruising: Increased susceptibility to (severe) bruising due to fragile skin and blood vessels.

• Vulnerability of Internal Organs: Heightened risk of rupture or injury to internal organs.

• Ligament Weakness: Increased likelihood of ligament injuries and joint dislocations and/or subluxations.

Understanding these manifestations is crucial for managing the challenges associated with EDS and providing appropriate care.

Common Associated Conditions

Individuals with EDS often face numerous comorbidities, some of which include: Dysautonomia/POTS, with symptoms like severe lightheadedness, fainting (syncope), tachycardia, brain fog, and temperature dysregulation. Gastrointestinal issues are prevalent, including functional bowel disorders, while Mast Cell Activation Syndrome (MCAS) can lead to rashes, hives, and allergic-type reactions. Additional complications can arise, such as heart and valve problems, glaucoma or retinal detachment, dental issues like gum disease and tooth loss, spine problems such as scoliosis and craniocervical instability, and chronic migraines and headaches.

The severity and combination of symptoms can vary widely across patients, even within the same EDS subtype, making diagnosis and management challenging. Understanding the specific type of EDS and associated conditions is crucial for effective treatment and improving the quality of life for those affected.

Our favorite (American) resource for Ehlers-Danlos Syndrome is the Ehlers-Danlos Society.

Sources: Mayo Clinic, Cleveland Clinic, NIH, Cedars Sinai, EDS.clinic, Clair Francomano, M.D., and The Ehlers-Danlos Society.