PART THREE: PROBLEMS, PREVALENCE AND RISK FACTORS

5.0 What Can Cause Ehlers-Danlos Syndromes?

EDS can be caused by:

• Being generally inherited through two known inheritance patterns:
  • Autosomal Dominant (AD): If you get the abnormal gene from only one parent, you can get the disease.
  • Autosomal Recessive (AR): Means two copies (i.e. from both parents) of an abnormal gene must be present in order for the disease or trait to develop.
• New (de novo) gene mutations that occurs in people with no history of the disorder in their family.

5.1 Why is it a Problem?

Connective tissue (discussed in Part Two) is what the body uses to provide strength and elasticity; normal connective tissue holds strong proteins that allow tissue to be stretched but not beyond its limit, and then safely return that tissue to normal. Connective tissue is found throughout the body, and EDS are considered structural problems.

For individuals with EDS, some or all of the tissue in the body can be pulled beyond normal limits causing damage. The problems resulting from this – aka having one’s body being built out of a protein that behaves unreliably – can be widespread and in a wide range of severity. It can manifest in places that seem unrelated until the underlying connection to EDS is recognised.

General issues with EDS include:

• Can be painful and disabling;
• It affects skin, wound healing, and joints;
• The effects worsen over time as hypermobile joints can be unstable, causing dislocations, subluxations (partial dislocation), arthritis, bursitis, tendonitis, and other musculoskeletal problems; and
• Hyperextensible skin is easily torn and does not repair itself well, causing pain and disfiguring scarring.

Another way of looking at the problems associated with EDS is:

Connective tissue dysfunction > hypermobility > pain > impaired movement patterns > decreased activity

The pain associated with EDS can lead to decreased movement, which can lead to:

• Decreased stamina;
• Impaired movement patterns;
• Atrophy of muscles;
• Decrease in joint control/stability;
• Decreased use of joint(s);
• Increased stress/strain on supporting structures of a joint(s);
• Increase in anxiety and depression;
• Fear of movement; and
• Decrease in functional abilities.

Finally, a diagnosis is important because, although EDS are not curable, they are treatable. Knowing that you have an EDS, and the sub-type, gives an indication of where problems might arise and why they are happening.

In summary, EDS can have a dramatic impact on an individual’s quality of life, providing significant challenges for daily, social, and recreational activities. Individuals with muscle hypotonia (The state of having hypotonic, reduced, muscle tone.) and joint instability with chronic pain may have to adjust lifestyle and professional choices accordingly. And, long-term chronic pain may result in the need for mental health services.

5.2 What are the Complications?

It is important to note that EDS have associated morbidity (A diseased state or symptom) and associated mortality (i.e. death) depending on the sub-type. Failure to treat EDS can lead to the exacerbation of long term sequelae (A negative aftereffect), including:

• Severe generalised joint hypermobility.
• Joint dislocation or recurrent subluxations.
• Limited physical activity or exercise capability.
• Limited normal daily activities.
• Poor wound healing and scarring.
• Susceptibility to bruising.
• Lax skin.
• Skin fragility.
• Decrease in endurance or deconditioning.
• Fear of movement and fear avoidance.
• Psychological and/or psychiatric issues (Depression, anxiety, and panic disorder are common).
• Fatigue (This is common and is sometimes more disabling than the pain).
• Lateral plantar nerve injury.
• Muscle atrophy and weakness.
• Muscle pain and/or muscle spasm.
• Impaired balance/decreased proprioception (Tend to report feeling clumsy and falling more often than healthy individuals).
• Abnormal or poor postural stability. Gait deviations. Problems with blood pressure and heart rate.
• Gastrointestinal problems.
• Difficulty eating and weight loss (Baeza-Velasco et al., 2016).
• Blindness or vision loss.
• Pain in joints or spine (usually chronic).
• Physical discomfort, such as low back pain or lumbo-pelvic pain.
• Disability.

The precise nature of any complications may depend on the EDS sub-type and the individual.

5.3 Hypermobility EDS

As hEDS makes up approximately 80-90% of all EDS, it is appropriate to discuss it further here.

It is, and has been, known by a number of different names including:

• Hypermobility Ehlers-Danlos Syndrome (hEDS);
• Ehlers-Danlos (Type III) – Hypermobility Syndrome;
• Type III EDS;
• EDS Hypermobility Type; and
• Ehlers-Danlos Hypermobility Syndrome. It is now generally accepted that ‘benign familial articular hypermobility syndrome’ and ‘joint hypermobility syndrome’ are identical to hEDS and no longer thought to represent unique conditions (Grahame, 1999; Tinkle et al., 2009).

hEds has been described as progressing in three distinct phases (Tinkle et al., 2017):

• ‘Hypermobility’ Phase:
  • Dominates the first several years of life with contortionism and propensity for sprains and dislocations.
  • Pain is often limited to lower limbs (i.e., persistent “growing pains”) but pain with fine motor or repetitive tasks such as handwriting is also commonly encountered.
  • Easy fatigability may be a feature.
  • Voiding dysfunction may be a feature.
  • Some hypermobile children experience developmental dyspraxia (or developmental co-ordination disorder), manifesting with mild hypotonia and non-specific developmental delay in gross and fine motor skills attainment.
• ‘Pain’ Phase:
  • Characterised by generalisation and progressive chronicity of musculoskeletal pain, which is often diagnosed as fibromyalgia.
  • Summation of other forms of chronic pain, such as pelvic pain (in women) and headache, as well as exacerbation of fatigue.
  • This phase typically starts in the second to the fourth decade of life.
  • Often associates with a variegated constellation of additional complaints, such as paresthesias (A sensation of pricking, tingling, or creeping on the skin that has no objective cause.), mixed and treatment-resistant functional gastrointestinal disorders, orthostatic intolerance, and pelvic dysfunction.
• ‘Stiffness’ Phase:
  • A generalised reduction of joint mobility dominates this phase.
  • Individuals usually experience significant reduction in their functionality due to the combination of disabling symptoms (e.g., pain and fatigue) as well as motor limitations due to the coexistence of reduced muscle mass and weakness, defective proprioception, prior injuries, and arthritis.
  • In this phase, observed in a few adults and elderly only, the symptomatology that appeared in the “pain” phase escalates and GJH is usually not appreciated.

It is important to note that not every individual experiences all three phases and the rate of transition between phases can be highly variable. It has also been suggested that a decrease of the Beighton Score (Section 4.4) in the symptomatic individual may be considered a proxy for disease evolution in hEDS (Tinkle et al., 2017).

“Some consider the hypermobility subtype of EDS to be the least severe because it is less likely to involve internal organs. However, these patients may experience the most debilitating musculoskeletal function.” (Laferrier et al., 2018, p.383).

Problems associated with hEDS include (Levy, 2018):

• Joint hypermobility:
  • Can be symptomatic or asymptomatic.
• Pain:
  • Can cause both acute and chronic pain, and contributes to disability.
• Skin and fascia:
  • In hEDS, the skin texture is characteristically soft, silky, or velvety to the touch. It may be semi-transparent so that veins and tendons are more easily visible than normal, but this is subtle in comparison with the skin transparency of vascular EDS.
  • The skin is more fragile than normal, but much less so than in the other types of EDS.
  • Easy bruising is common but poorly defined.
• Fatigue:
  • One of the most common complaints among those with hEDS.
  • Chronic fatigue (present for more than six months) in hEDS includes bodily and mental fatigue which only minimally improves with rest and often fits well into the diagnostic criteria of chronic fatigue syndrome (CFS) (Rowe et al., 1999). “A proportion of those with CFS likely have EDS that has not been identified.” (Hakim et al., 2017b).
  • It is multifactorial with contributing factors including pain, sleep disturbance, dysautonomia, medications, and/or allergies.
  • It has been associated with greater pain, functional impairment, and psychological distress as well as decreased quality of life.
  • Research suggests it may also be a factor in musculoskeletal pain and injury.
  • Exercise to the point of physical fatigue has been shown to alter kinematics, postural stability, and coordination, which may increase the risk of direct injury and also the risk of falls causing secondary injury.
  • Exercise-induced fatigue increases knee laxity (Skinner et al., 1986), which may also increase the risk of knee injury.
  • Fatigue is also associated with reduced ground reactive force during gait, suggestive of decreased proprioception (Celletti et al., 2012), which could also increase the risk for falls and injury.
• Cardiovascular:
  • Mild dilation of the aortic root may develop in up to one-third of children or young adults (Wenstrup et al., 2002; McDonnell et al., 2006; Atzinger et al., 2011), but is unlikely to require any specific treatment.
  • POTS, NMH, and orthostatic intolerance are common manifestations in hEDS (discussed in Section 10.3).
  • Mitral valve prolapse (MVP) may be a potential clue for hEDS, although the true clinical significance is not yet known.
• Gastrointestinal disorders:
  • The relevance of gastrointestinal manifestations in hEDS is increasing in both scientific and clinical perspectives.
  • Manifestations variably include gastroesophageal reflux, heartburn, bloating, recurrent abdominal pain, irritable bowel syndrome, constipation, and diarrhoea.
  • Dysphagia may be a further common complaint.
  • Constipation with or without other features of voiding dysfunction is usually the earliest sign of gastrointestinal involvement, which tends to manifest with multiple, sometimes severely disabling symptoms at any age.
  • The exclusion of common comorbidities, such as coeliac disease, lactose intolerance, and Helicobacter pylori infection, is reasonable at first examination.
  • Preliminary results suggest an increased rate of coeliac disease (Danese et al., 2011; Laszkowska et al., 2016) and eosinophilic esophagitis (Abonia et al., 2013) in hEDS, but additional studies are required to determine the significance of these potential associations.
• Dysautonomia:
  • A disorder of the autonomic nervous system that causes disturbances in all or some autonomic functions and may result from the course of a disease or from injury or poisoning (discussed in Section 10.3).
  • Typical signs and symptoms include tachycardia, hypotension, gastrointestinal dysmotility, disturbed bladder function, and sweating regulation (Hakim et al., 2017a).
• Bone Mass:
  • May be associated with low bone mineral density (osteopenia) (Coelho et al., 1994).
  • No convincing evidence that hEDS is associated with osteoporosis or fragility fractures, especially in children.
• Osteoarthritis:
  • It is possible that an increase in the prevalence of osteoarthritis is due to the same underlying collagenopathy or by repetitive trauma that commonly occurs in joint hypermobility and altered joint mechanics (Bird et al., 1978; Grahame, 1989; Klemp, 1997).
  • Knee hypermobility is common among patients with knee osteoarthritis (Dolan et al., 2003; van der Esch et al., 2006; Gurer et al., 2016).
• Headaches:
  • Headaches in hEDS vary by type and severity.
  • Cervical spine hypermobility is associated with headaches.
  • Craniocervical junction instability or simply the musculature strain throughout the upper body can cause widespread spasms and muscular tension leading to headaches.
  • Temporal headaches, unilateral or bilateral, may again be related to muscular dysfunction but involving the temporomandibular joint.
  • Such headaches can be associated also with ear symptoms such as pain, sense of fullness, or tinnitus.
  • Those individuals with dysautonomia, orthostatic intolerance, or POTS can also complain of intense pounding headaches (discussed in Section 10.3).
  • Medications and medication overuse can also be responsible for headaches in this population.
• Temporomandibular Joint (TMJ) and Dental Issues:
  • More common in women than men.
  • The jaw in hEDS is often hypermobile until such time that damage occurs in the TMJ.
  • Jaw sounds, locking, dislocation, bruxism, and temporal headaches are also frequently described in this population.
  • There is an association between temporomandibular joint dysfunction (TMD) and generalised joint hypermobility.
  • TMJ pain is often associated with palpable pain of the neck and shoulder musculature, widespread pain, chronic illness, and female gender (Sipila et al., 2011).
  • Periodontitis (inflammation of the supporting structures of the teeth) may be common.
  • The teeth in hEDS are described with slightly altered morphology with higher cusps and deeper fissures of the premolars and molars with shortened roots.
  • Enamel hypoplasia (a condition of arrested development in which an organ or part remains below the normal size or in an immature state).
• Spine:
  • Postural kyphosis is commonly encountered in those with hEDS (el-Shahaly & el-Sherif, 1991).
  • Scoliosis, although often mild and requiring no intervention, is also common occurring in up to 50% (Ainsworth & Aulicino, 1993; Stanitski et al., 2000; Adib et al., 2005; Czaprowski, 2014; Stern et al., 2016).
  • Cervical hypermobility has been associated with headaches and hEDS (Rozen et al., 2006).
• Gynaecologic Issues:
  • Issues can include mucosal problems with genital area, heavy menstrual bleeding (menorrhagia), and painful intercourse.
• Pelvic Dysfunction:
  • Pelvic floor disorders include urinary incontinence, pelvic organ prolapse, and other sensory and emptying abnormalities.
  • Childbirth has a very substantial impact on a woman’s probability of developing pelvic floor disorders.
• Pregnancy and Childbirth:
  • Research is mixed on whether hEDS and several pregnancy-related complications are associated.
  • Premature birth has been reported as more common among individuals with EDS than in the general population, but this appears to be primarily among women with classic EDS.
• Urinary System:
  • Children may have an increase in daytime and night-time urinary incontinence as well as urinary tract infections (UTIs) (De Kort et al., 2003).
  • Voiding dysfunction was also significantly associated with GJH in children but this is unclear if this is secondary to constipation (Kajbafzadeh et al., 2014).
  • UTI’s and urinary tract dysfunction may be more common in girls (Adib et al., 2005).
  • Vesicouretal reflux can also be common in children with hEDS (Beiraghdar et al., 2013).
• Sleep Disturbance:
  • Many individuals with hEDS report poor sleep including insomnia and unrefreshing sleep (Verbraecken et al., 2001; Hakim and Grahame, 2004; Murray et al., 2013).
  • Some also report restless legs syndrome and sleep apnoea (Guilleminault et al., 2013).
  • Fibromyalgia is also a common comorbidity (Ofluoglu et al., 2006; Ting et al., 2012) and is strongly associated with sleep disturbance, including abnormal sleep architecture (Dauvilliers and Touchon, 2001; Besteiro Gonzalez et al., 2011).
  • Other factors to consider include pain, dysautonomia, poor sleep hygiene, and medications.
• Mast Cell Activation Disorder (MCAS):
  • MCAS refers to an increased number of mast cells, increased mast cell mediators (e.g. histamine, tryptase, etc.), or both.
  • The clinical symptoms of MCAS include flushing, pruritis (itchy skin that makes you want to scratch), hypotension, asthma, diarrhoea, abdominal bloating, and cramping.
  • Those with EDS report a higher incidence of food sensitivities suggestive of histamine reaction (Berglund, 2015).
  • Regardless of any possible association, the presence of MCAS in hEDS might complicate the known symptoms of POTS, chronic fatigue, and gastrointestinal manifestations.
• Psychiatric:
  • Psychological dysfunction and emotional problems, including depression, anxiety, affective disorder, low self-confidence, negative thinking, hopelessness, and desperation, are also common among those with EDS (Hagberg et al., 2004; Castori et al., 2010b; Baeza-Velasco et al., 2011; Branson et al., 2011; Rombaut et al., 2011a; Berglund et al., 2015; Sinibaldi et al., 2015; Hershenfeld et al., 2016).
  • These problems may exacerbate the pain experience, as well as other organ system manifestations (especially gastrointestinal and autonomic).
• Quality of Life:
  • Gastrointestinal disorders correlate with a poorer quality of life in people with EDS.
  • Physical pain, psychological discomfort, and handicap has considerable impact on health-related quality of life in people with EDS.
  • Adults with hEDS reporting neck and shoulder pain have a significant association with generalised pain and a decreased health-related quality of life (Johannessen et al., 2016).
  • Children with hEDS and fatigue experience poor health-related quality of life (Pacey et al., 2015).
  • Research suggests a significant disability related to pain, fatigue, and psychological distress in hEDS (Scheper et al., 2016).

6.0 Who Can Be Affected By Ehlers-Danlos Syndromes?

EDS are known to affect both males and females of all racial and ethnic backgrounds.

7.0 Prevalence and Risk Factors

Statistics on prevalence include:

• Was once considered to be a rare condition at 1/400,000-500,000 (Laferrier et al., 2018).
• A minimum prevalence of 1/5,000 for all types of EDS collectively (Steinman et al., 2002).
• hEDS makes up approximately 80-90% of EDS cases (Tinkle et al., 2017).
• The prevalence of hEDS ranges from 1/5,000 to 1/20,000 (Stanitski et al., 2000).
• hEDS and classical EDS combined account for more than 90% of cases (Laferrier et al., 2018).
• Vascular EDS is the third most common type affecting approximately 1 in 250,000 people (Laferrier et al., 2018).
• It has been proposed that symptomatic generalised joint hypermobility has a prevalence of approximately 7.5/1,000 to 20/1,000 (0.75 to 2.0%) based on 10% of the individuals with GJH that may develop related symptoms in their lifetime (Hakim & Sahota, 2006).
• Based on data obtained from a large epidemiological study undertaken on a population of 12,853, 3.4% had joint hypermobility and widespread pain which was used as a proxy for hEDS (Mulvey et al., 2013).
• It has been suggested that hEDS is likely the most common systemic inherited connective tissue disorder in humans which translates to (approximately) (Tinkle et al., 2017):
  • 2 million in the United Kingdom;
  • 10 million in the United States;
  • 17 million in Europe; and
  • 255 million affected worldwide.
  • “…currently there are more than 1.5 million cases of EDS worldwide when taking into account all subtypes, with this number likely to increase substantially.” (Laferrier et al., 2018, p.382).
• hEDS may affect more women than men, at least in adults (Castori et al., 2010), with ratio ranges from 8-9:1 to 2:1 depending upon how the individuals were selected in the studies.
• “However, in the general population, as children enter puberty, joint mobility tends to increase in females and decrease in males.” (Tinkle et al., 2017, p.51).
• Classical EDS (Malfait et al., 2018):
  • Approximately 50% of affected individuals have an affected parent.
  • Approximately 50% of affected individuals have the disorder as the result of a de novo pathogenic variant.
  • Each child of an affected individual has a 50% chance of inheriting the pathogenic variant.
  • In addition to the genetic information passed on from generation to generation, each of us is born with a small number of novel genetic changes – de novo mutations – that occurred either during the formation of:
    • The gametes (A mature haploid male or female germ cell which is able to unite with another of the opposite sex in sexual reproduction to form a zygote.); or
    • Postzygotically (A change in an organism’s genome that is acquired during its lifespan, instead of being inherited from its parent(s) through fusion of two haploid gametes.).
  • “Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age.” (Acuna-Hidalgo et al., 2016, p.241).
  • “However, it is likely that some individuals with milder manifestations of the disease, previously classified as EDS type II, do not come to medical attention and thus go undetected.” (Malfait et al., 2018).

Risk factors for EDS include:

• Family history of joint hypermobility or EDS.
  • It is a heritable condition, meaning passed on from parent to child.
• Genetic mutations.
  • Novel mutations continue arising throughout post-natal and adult life in both somatic and germ cells. Only mutations present in the germ cells can be transmitted to the next generation (Acuna-Hidalgo, 2016).

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