An In-Depth Look Into Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome affects thousands of people around the world. What is it?

By Erin Rought

Ehlers-Danlos syndrome (EDS) is a group of thirteen rare genetic disorders that mainly affect connective tissues including skin, joints, and blood vessel walls. Connective tissues hold the body’s structure in place and support organs. People with EDS have an impaired production of strong collagen, leading to weaker and less supportive connective tissues. It is estimated that around 1 in 5,000 people have EDS. 

Types of EDS: 

EDS encompasses a wide range of subtypes, each with its own symptoms, treatment approaches, and underlying genetic causes. The most common type is hypermobile Ehlers-Danlos syndrome (hEDS), which accounts for around 90% of all EDS cases. Individuals with hEDS experience increased joint mobility, which can lead to joint instability, pain, and an increased risk of injuries.  

Classical EDS (cEDS) is the second most prevalent type of EDS, it affects approximately 1 in 20,000-40,000 people (about twice the seating capacity of Madison Square Garden). Characteristic features of cEDS include skin hyperextensibility, fragility, and atrophic scarring, as well as joint hypermobility and instability. 

Vascular Ehlers-Danlos syndrome (vEDS) is the third most common type, affecting every 1 in 100,000-200,000 people.  People with vEDS often have distinct facial features (such as thin nose, small earlobes, and prominent eyes), as well as thin, translucent skin that bruises easily. Vascular EDS weakens the aorta, arteries, and other large blood vessels, leaving sufferers with an increased risk of life-threatening ruptures. 

Other less common types of EDS include periodontal EDS (pEDS), kyphoscoliosis EDS (kEDS), spondylodysplastic EDS (spEDS), arthrochalasia EDS (aEDS), musculocontractural EDS (mcEDS), classical-like EDS (clEDS), dermatosparaxis EDS (dEDS), cardiac-valvular EDS (cvEDS), and brittle cornea syndrome (BCS). Each of these subtypes affects less than 1 in 1,000,000 people (about the population of Delaware), and have their own unique set of symptoms, genetic causes, and management strategies. 

Symptoms: 

There are several symptoms of Ehlers-Danlos syndrome, including: Overly flexible (hypermobile) joints; soft skin; bruising easily; unusual scarring; taking long to heal after a cut or small wound; joint and muscle pain; fatigue (feeling tired all the time); and difficulty concentrating. A person can feel these symptoms in any of their connective tissues (skin, joints, muscles, blood vessels). The rarer the form becomes, the more distinct and sometimes deadly the symptoms are. 

Vascular EDS is usually accompanied by easy and unusual bruising: arterial aneurysm, dissection, and ruptures often before the age of 40; carotid-cavernous sinus fistula formation without trauma; bowel perforation; spontaneous pneumothorax; uterine rupture during the third trimester of pregnancy; and characteristic facial features. 

Periodontal EDS means you have severe, early-onset periodontitis; lack of attached gingiva; pretibial plaques; easy bruising; as well as regular joint hypermobility, skin hyperextensibility, and skin fragility. 

Kyphoscoliotic EDS comes with an array of symptoms, such as: Congenital or early-onset kyphoscoliosis; Low muscle tone; joint hypermobility; delayed motor development; eye problems; foot deformities; soft, stretchy, or fragile skin; easy bruising; and hearing loss. 

Spondylodysplastic EDS often means leads to a person having a short stature; muscle hypotonia; joint hypermobility and contractures; skin hyperextensibility and atrophic scarring; as well as various facial and skeletal features that depend on the gene variant. 

Brittle Cornea Syndrome means the person has corneal perforation; blue sclerae; joint hypermobility; kyphoscoliosis; developmental dysplasia of the hip; hearing loss; and soft or translucent skin. 

Arthrochalasia EDS includes congenital bilateral hip dislocation; generalized joint hypermobility; recurrent joint dislocations and subluxations; skin hyperextensibility and fragility; muscle hypotonia; delay in motor development; spinal issues; easy bruising and atrophic scarring; foot deformities.  

Musculocontractural EDS shows long, slender fingers with fine palmar creases; congenital multiple contractures; progressive talipes deformities; spinal deformities; skin hyperextensibility and fragility; easy bruising and atrophic scarring; delay in motor development; muscle hypotonia and weakness; joint dislocations; and pectus deformities. 

Dermatosparaxis EDS causes a person to have various craniofacial features; short limbs; joint hypermobility; doughy skin texture; umbilical hernia at birth; severe bruising; and severe skin fragility and loose access skin. 

Cardiac-Valvular EDS causes, well, severe cardiac-valvular disease, as well as skin hyperextensibility; atrophic scarring; and joint hypermobility. 

Diagnosis: 

Each type of EDS has its own clinical diagnostic criteria, and if a person meets the criteria, they get a genetic test done, except for hEDS due to hypermobile eds not having a known gene deficiency yet. 

For the most common type of EDS a person must meet all three criteria (1,2 and 3), which is discovered using the pediatric diagnostic framework. The criterion is generalized joint hypermobility; two or more of the following features (A, B, and C) must be present, and ALL prerequisites must be met. The diagnostic framework asks five questions, and diagnoses hypermobility based on those.

The first question is “Is generalized joint hypermobility present,” where they are given a point (up to nine points) for each finger that can do the following: Can the pinkies bend beyond 90 degrees? Can their thumb touch your forearm? Do their elbows extend upwards an extra 10 degrees? When they lock their knees, does the lower part of either leg extend more than 10 degrees forward? Lastly, can they place their hands flat on the floor in front of their feet without bending their knees.

A score of 6 or more is evidence of generalized joint hypermobility in children before puberty. The second question is “Are musculoskeletal complications presents?” where they have activity-related pain that is not chronic in frequency or duration, recurrent joint dislocations, recurrent joint subluxations in the absence of trauma and/or frank subluxation on physical exam in more than one joint and soft tissue injures either needing surgical repair or minor tendon/ligament tears. The third question “is the person affected by comorbidities?” is asking does it have an impact on their life. Do they have chronic pain? Do they have chronic fatigue? Do they have functional gastrointestinal disorders? Do they have function bladder disorders? Do they have anxiety? Do they have primary dysautonomia? The fourth question, “Is there skin and tissue involvement”, refers to the symptoms of the skin: unusually soft skin, mild skin hyperextensibility, unexplained stretch marks, atrophic scarring, bilateral piezogenic papules of the heel, and recurrent hernia (or hernia in more than one site). Lastly, “Have other conditions that could cause the person’s symptoms have been excluded?” 

For classical EDS, a person must meet major criterion one AND major criterion two or meet major criterion one and three or more minor criteria. The major criteria are Skin hyperextensibility; atrophic scarring; and generalized joint hypermobility. The minor criteria are easy bruising; soft, doughy skin; skin fragility (or traumatic splitting); Molluscoid pseudotumor; Subcutaneous spheroids; Hernia (or history thereof); epicanthal folds; Complications of joint hypermobility; and family history of a first-degree relative who meets clinical criteria. Once a person has met the criteria, they then undergo genetic testing to see if they have the affected genes/proteins of that type of EDS. 

For vascular EDS, a person must meet one of the major criteria or several minor criteria, especially if they are under the age of forty. The major criteria are: Family history of vEDS with a documented causative variant in COL3A1; arterial rupture at a young age; spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology; uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears; and carotid-cavernous sinus fistula (CCF) formation in the absence of trauma. The minor criteria are: Bruising unrelated to showed trauma and/or in unusual sites such as the cheeks and back; spontaneous pneumothorax; acrogeria; talipes equinovarus; congenital hip dislocation; hypermobility of small joints; tendon and muscle ruptures; keratoconus; gingival recession and gingival fragility; and early on-set varicose veins. 

For periodontal EDS, a person must meet either major criterion 1 and two other major criteria and one minor criterion or major criterion 2 and two other major criteria and one minor criterion. The major criteria are: severe and intractable periodontitis of early onset (childhood or adolescence); lack of attached gingiva; pretibial plaques; and family history of a first-degree relative who meets the clinical diagnostic criteria for pEDS. The minor criteria are easy bruising; joint hypermobility, mostly distal joints; skin hyperextensibility and fragility, abnormal scarring (wide or atrophic); increased rate of infections; hernias; marfanoid facial features; acrogeria; and prominent vasculature. 

For kyphoscoliotic EDS, a person must meet major criterion one, major criterion two, and major criterion three or they must meet major criterion 1 and major criterion 2 and three minor criteria (general or gene-specific).  The major criteria are congenital muscle hypotonia; congenital or early onset kyphoscoliosis (progressive or non-progressive); and generalized joint hypermobility with dislocation/subluxations (shoulders, hips, and knees in particular). The minor criteria are skin hyperextensibility; easy bruising skin; rupture/aneurysm of a medium-sized artery; osteopenia/osteoporosis; blue sclerae; hernia (umbilical or inguinal); pectus deformity; marfanoid habitus; talipes equinovarus; and refractive errors (myopia, hypermetropia).   The gene-specific minor criteria are based on the two genes that have been connected to kEDS. PLOD1 has the criteria of skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring); scleral and ocular fragility/rupture; microcornea; and facial dysmorphology. FKBP14 has the criteria of: congenital hearing impairment (sensorineural, conductive, or mixed); Follicular hyperkeratosis; Muscle atrophy; and Bladder diverticula. 

For spondylodysplatic EDS, a person must meet major criterion 1 and major criterion 2 and have characteristic radiographic abnormalities and at least two other minor criteria (general or gene-specific). The major criteria are: Short stature (progressive in childhood); muscle hypotonia (ranging from severe congenital to mild later onset); and bowing of limbs. Minor criteria are skin hyperextensibility, soft, doughy skin, thin translucent skin; pes planus; delayed motor development; osteopenia; and delayed cognitive development. The criteria for B3GALT6 are: kyphoscoliosis (congenital or early onset, progressive); joint hypermobility (generalized or restricted to distal joints, with joint dislocations); joint contractures (congenital or progressive) (especially hands); peculiar fingers (slender, tapered, arachnodactyly, spatulate, with broad distal phalanges); talipes equinovarus; characteristic craniofacial features; tooth discoloration, dysplastic teeth; characteristic radiographic findings; osteoporosis with multiple spontaneous fractures; ascending aortic aneurysm; and lung hypoplasia, restrictive lung disease. The criteria for B4GALT7 are: radioulnar synostosis; bilateral elbow contractures or limited elbow movement; generalized joint hypermobility; single transverse palmar crease; characteristic craniofacial features; characteristic radiographic findings; severe hypermetropia; and clouded cornea. For SLC39A13 the criteria are: protuberant eyes with bluish sclerae; hands with finely wrinkled palms; atrophy of the thenar muscles, and tapering fingers; hypermobility of distal joints; and characteristic radiologic findings. 

For Brittle Cornea Syndrome, a person must meet major criterion one and at least one other major criterion or they have to meet major criterion one and at least three minor criteria. The major criteria are thin corneas, without rupture; early onset progressive keratoconus; early onset progressive keratoglobus; and blue sclerae. The minor criteria are: enucleation or corneal scarring as a result of previous rupture; progressive loss of corneal stromal depth, especially in the central cornea; high myopia, with normal or moderately increased axial length; retinal detachment; deafness, often with mixed conductive and sensorineural components, progressive, higher frequencies often more severely affected (“sloping” pure tone audiogram); hyper-compliant tympanic membranes; developmental dysplasia of the hip; hypotonia in infancy, usually mild if present; scoliosis; arachnodactyly; hypermobility of distal joints; pes planus, hallux valgus; mild contractures of fingers (especially 5th); and soft, velvety skin, translucent skin. 

People with arthrochalasia Ehlers Danlos need to meet either major criterion 1 and major criterion 3 or meet major criterion 1 and major criterion 2 and at least two minor criteria. The major criteria are: congenital bilateral hip dislocation; severely generalized joint hypermobility, with multiple dislocations/subluxations; and skin hyperextensibility. The minor criteria are muscle hypotonia; kyphoscoliosis; radiologically mild osteopenia; tissue fragility, including atrophic scars; and easily bruisable skin.  

Musculocontractural Ehlers-Danlos syndrome is diagnosed differently at birth and early childhood than it is for adolescence and adulthood. For a person getting diagnosed with mcEDS at birth or during early childhood, they must meet major criterion one and major criterion twp. When a person tries to get diagnosed with mcEDS in adolescence and adulthood, they must meet major criterion one and major criterion three. The major criteria are: congenital multiple contractures, normally adduction-flexion contractures and/or clubfoot; characteristic craniofacial features that are clear at birth or in early infancy; characteristic cutaneous features such as skin hyperextensibility, easy bruisability; skin fragility with atrophic scars; and increased palmar wrinkling. The minor criteria are: recurrent/chronic dislocations; pectus deformities (flat, excavated); spinal deformities (scoliosis, kyphoscoliosis); peculiar fingers (tapering, slender, cylindrical); progressive talipes deformities (valgus, planus, cavum); large subcutaneous hematomas; chronic constipation; colonic diverticula; pneumothorax/pneumohemothorax; nephrolithiasis/cystolithiasis; hydronephrosis; cryptorchidism (in males); strabismus; refractive errors (myopia, astigmatism); and glaucoma/elevated intraocular pressure. 

A person must meet all three major criteria AND have a family history compatible with the inheritance for classic-like EDS. The major criteria are skin hyperextensibility, with velvety skin texture and absence of atrophic scarring; generalized joint hypermobility, with or without dislocations; and easily bruisable skin/spontaneous ecchymoses. The minor criteria are foot deformities; edema in the legs in the absence of cardiac failure; mild proximal and distal muscle weakness; axonal polyneuropathy; atrophy of muscles in hands and feet; acrogeric hands, mallet fingers, clinodactyly, brachydactyly; vaginal/uterus/rectal prolapse. 

Before the genetic test, dermatosparaxis EDS is diagnosed by a person meeting major criterion one and major criterion two and at least one other major criterion or a person meeting major criterion one and major criterion two and at least three minor criteria. The major criteria are: extreme skin fragility with congenital or postnatal skin tears; characteristic craniofacial features, which are evident at birth or early infancy or evolve later in childhood; redundance, almost lax skin, with excessive skin folds at the wrists and ankles; increased palmar wrinkling; severe bruisability with a risk of subcutaneous hematomas and hemorrhage; umbilical hernia; postnatal growth mental issues; short limbs, hands, and feet; and perinatal complications due to connective tissue fragility. The minor criteria are: soft and doughy skin texture; skin hyperextensibility; atrophic scars; generalized joint hypermobility; complications of visceral fragility; delayed motor development; osteopenia; hirsutism; tooth abnormalities; refractive errors (myopia, astigmatism); and strabism. 

A person suspected of Cardiac-Valvular Ehlers-Danlos has to meet major criterion 1 and family history compatible with autosomal recessive inheritance and at least one other major criterion, or they must meet major criterion 1 and family history compatible with autosomal recessive inheritance and at least two minor criteria. The major criteria are: Severe progressive cardiac-valvular problems (aortic valve, mitral valve); Skin involvement (skin hyperextensibility, atrophic scars, thin skin, easy bruising); and joint hypermobility (generalized or restricted to small joints). The minor criteria are: Inguinal hernia; pectus deformity; joint dislocations; and foot deformities. 

Complications: 

The complications associated with EDS can be severe and life-threatening, especially depending on the subtype. People who have vEDS are at an increased risk of an arterial aneurysm, dissection, and ruptures, which can be fatal. Kyphoscoliosis EDS is also associated with those life-threatening ruptures.  Individuals who have dermatosparaxis EDS may experience bladder, diaphragmatic, or rectal ruptures. 

Preventions/management: 

There is not much that can be done to prevent EDS. If a person knows they have EDS, they can talk to a geneticist about the odds of their kids receiving it too. Treatment/management of EDS varies from person to person because it affects everyone who has it differently. Most of the time, people who have EDS require multiple providers with different specialties to make a plan that works best to help minimize the pain caused by their symptoms. Some of the most common treatments for EDS are wearing sunscreen and using mild soaps to protect the skin; physical therapy; wearing braces; not doing any heavy lifting; no high-impact exercises; and no contact sports. 

Research: 

There is currently a plethora of different research being done on Ehlers-Danlos Syndrome. The Ehlers-Danlos Syndrome Research Foundation (EDSRF) is currently focusing on “Prevalence of Ehlers Danlos Syndromes and Autonomic Dysfunction in Patients with Mannose Binding Lectin Deficiency,” “Economic Impact of Ehlers-Danlos Syndrome: Patient Perspective,” “The Impact of Underinvestment in Ehlers-Danlos Syndrome,” “Prevalence of Ehlers-Danlos Syndromes in the United States.”  Last year, they rewarded grants for the following research “Risk of Severe Disease and Post-Acute SARS-CoV-2 within Connective Tissue Diseases” which received $200,000 two year grant, “Toward Artificially Intelligent Wearable Neuromodulation Systems to Address Postural Orthostatic Intolerance and Other Autonomic Disturbances in Humans with Hypermobile-type Ehlers-Danlos Syndrome” which received a $100,000 two year grant, and “Risk Factors for Long Covid” which received a $10,000 one year grant. Their next batch of research on a couple topics: impact, diagnosis, and management of EDS; interventions, targeted therapies that are solution-based and impactful; studies with meaningful, near-immediate effects on clinical practice; musculoskeletal studies; long-term outcomes of spine and joint surgeries, and non-surgical interventions including complications and infection rates; EDS and HSD comorbidities and the impact of these comorbidities; and epidemiology, natural history, or clinical history. 

Conclusion: 

Ehlers-Danlos syndrome is a rare condition that has a lot of scary symptoms and complications. There is still a lot of research needing to be done to help find a better treatment plan than “don’t do this” and “don’t do that”. But, even though a lot of research is still needed, people with EDS shouldn’t be overly worried about their condition. A person with EDS can still live a long and normal life if they stay updated on their treatment plans and go seek medical help the second it is necessary. 

Wanna chat? Email Erin at er965821@ohio.edu or follow her on Instagram @attitudesgenetic.