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Research – Ehlers Danlos Syndrome

Brief	Please provide information on the condition: Ehlers Danlos. I understand that there are two variants to this condition. What are the diagnostic markers, how does it present functionally? What are the evidence based treatments for this condition? What is the incidence of EDS as a primary condition? What kinds of conditions may comorbidly exist? Also please provide a list of possible experts in EDS in Australia.
Date	08/06/2021
Requester(s)	Shannon `redacted: s22(1)(a)(ii) - irr` – Assistant Director (TAB/AAT)
Researcher	Jane `redacted: s22(1)(a)(ii) - irrelev` – Research Team Leader (TAB)
Cleared

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The contents of this document are OFFICIAL

1 Contents

2 Types and Clinical Presentation ………………………………………………………………………………………… 3

2.1 Classical ………………………………………………………………………………………………………………….. 3

2.2 Classical-like ……………………………………………………………………………………………………………. 3

 2.2.1 Cardiac-valvular type ...................................................................................................... 4

 2.2.2 Vascular type ................................................................................................................... 4

 2.2.3 Hypermobility type ......................................................................................................... 4

 2.2.4 Arthrochalasia type ......................................................................................................... 5

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 2.2.5 Dermatosparaxis type ..................................................................................................... 5

 2.2.6 Kyphoscoliotic type ......................................................................................................... 5

 2.2.7 Brittle cornea syndrome ................................................................................................. 6

 2.2.8 Spondylodysplastic type ................................................................................................. 6

 2.2.9 Musculocontractural type ............................................................................................... 6

 2.2.10 Myopathic type ............................................................................................................... 6

 2.2.11 Periodontal type.............................................................................................................. 7

3 Evidence Based Treatments ……………………………………………………………………………………………… 7

3.1 Treatment of manifestations …………………………………………………………………………………….. 7

3.2 Prevention of primary manifestations ………………………………………………………………………… 7

3.3 Prevention of secondary complications ………………………………………………………………………. 7

3.4 Surveillance …………………………………………………………………………………………………………….. 7

Agents/circumstances to avoid …………………………………………………………………………………….–––––

3.5 Genetic counselling ………………………………………………………………………………………………….. 8

3.6 Surgery …………………………………………………………………………………………………………………… 8

4 Prevalence ……………………………………………………………………………………………………………………… 8

5 Co-existing Conditions …………………………………………………………………………………………………….. 8

6 List of possible experts in Australia……………………………………………………………………………………. 9

7 References …………………………………………………………………………………………………………………… 10

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2 Types and Clinical Presentation

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inheritable connective tissue disorders attributed to mutations in connective tissue genes [1]. These mutations cause defects in collagen. Collagen, a connective tissue protein that acts like glue, gives strength to the body and provides support and elasticity for movement. Thus, the altered gene affects the mechanical properties of skin, joints, ligaments, and blood vessels [1].

The International EDS Consortium provided a revised classification of EDS in 2017 which includes 13 subtypes [2, 3]. Vast genetic heterogeneity and phenotypic variability exists, and subtypes often overlap [3]. The condition is often diagnosed based upon the family history and clinical criteria, including the degree and nature of involvement of skin, joints, skeleton, and vasculature [3, 4]. Each subtype and their characteristic manifestations are provided below.

2.1 Classical

Classical EDS (formerly EDSI and EDSII) is associated with the primary problems such as:

Skin hyper-extensibility
Joint laxity
Fragile blood vessels.

Scars are very thin, discoloured, and stretch with time. Such paper-like (papyraceous) scarring occurs especially over prominent bony pressure points such as the knees, elbows, shins and forehead. Joint hypermobility accidents (subluxations and dislocations) are generally easily managed. Additional findings may include the formation of small, fleshy, skin growths called ‘molluscoid pseudo-tumours’ or hard, round, movable lumps under the skin called ‘calcified spheroids’.

Some individuals with this subtype may have heart complications including

Deformity of heart valves (especially the mitral/bicuspid valve between the atrium and the ventricle of the left side).
Valve dysfunction can result in remodelling of the heart’s architecture and with time congestive heart failure (pump insufficiency).
Dilatation of the aorta and increased risk also for aortic dissection. Aortic dissection is an immediate emergency that can result in acute heart failure.

2.2 Classical-like

Classical-like EDS is similar in clinical course to classical EDS (described above). However, genetic causes of classical EDS and classical-like EDS differ (described below).

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2.2.1 Cardiac-valvular type

Cardiac-valvular type EDS is a rare subtype of EDS wherein patients may have minor signs of EDS with severe defects to their aorta, requiring surgical interventions.

2.2.2 Vascular type

Vascular type EDS (formerly EDSIV), can be identified at birth with:

In childhood, and pneumothorax (collection of air between the lung and chest wall, impairing proper lung inflation) are commonly experienced and are indicative of this syndrome. Individuals with vascular EDS may also have:

Noticeable clubfoot deformities
Dislocation of the hips
Inguinal hernia (partial slip of intestine beyond the abdominal wall)
Pneumothorax (collection of air between the lung and chest wall, impairing proper lung inflation)
Abnormally decreased levels of fatty tissue under skin layers (subcutaneous adipose tissue) of the hands, arms, legs, feet, and face. Thus, some affected individuals may have a characteristic facial appearance. Cheeks are often taught and hollow. Lips and nose are often thin. Eyes are relatively prominent
Skin of the hands and feet may appear prematurely aged (acrogeria).
Arterial dissection and rupture, intestinal perforation, and uterine rupture.
Carotid-cavernous sinus fistula
Severe headaches
Seizures
Increased risk of stroke
Early onset of varicose veins
Acute pain in the abdominal or flank area may indicate arterial or intestinal rupture
Pregnancies should be considered higher risk and watch closely for arterial and uterine ruptures

The median life expectancy for vascular EDS is 50, but with careful surveillance and management of complications this age can be well extended.

2.2.3 Hypermobility type

Hypermobility type EDS (formerly EDSIII) comes with a defined set of complications to be managed but is generally a less severe form of the syndrome. For example, aortic root dilation is usually minimal and does not significantly increase the risk for dissections. The major complications to patients with hypermobility EDS are musculoskeletal in nature.

Frequent joint dislocation.

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Degenerative joint disease are common and associated with a baseline chronic pain, which affects both physical and psychological wellbeing.
Problems with the autonomic nervous system, responsible for regulating body functions and the fight-or-flight response, are common.
- Orthostatic intolerance, significant light-headedness on standing, due to a slowed response by their circulatory system to compensation against blood pressure and flow changes with shifts in body position.
Bowel disorders are also more common with this condition, especially functional dyspepsia (indigestion), and irritable bowel syndrome.
Psychological impairment and mood problems.

2.2.4 Arthrochalasia type

Arthrochalasia EDS (formerly EDSVII, A and B) is associated with the lifelong risk for the dislocation of multiple major joints concurrently. This condition makes achieving mobility significantly challenging. It is important to identify as early in life as possible as it carries consequences of physical disability with older age. Newborns may demonstrate severe muscular hypotonia and a bilateral dislocation of the hips at birth and might be difficult to distinguish from Kyphoscoliotic EDS (described below).

2.2.5 Dermatosparaxis type

Patient with dermatosparaxis EDS (formerly EDSVIIC) tend to show a set of common body features. These include:

Short stature and finger length
Loose skin of the face, with comparatively full eyelids
Blue-tinged whites of the eye (sclera)
Skin folds in the upper eyelids (epicanthal folds)
Downward slanting outer corners of the eyes (palpebral fissures)
Small jaw (micrognathia).

A major complication of dermatosparaxis EDS is herniation, the improper displacement of an organ through the tissues holding it in proper position. Hernias are especially common after certain surgeries, for example wherein there is an incision into the muscles of the abdomen. Due to the lengthy wound-healing process, intestinal contents may bulge through incisions. Patients with dermatosparaxis EDS are also prone to ruptures in the diaphragm and bladder.

2.2.6 Kyphoscoliotic type

Kyphoscoliotic EDS is accompanied by:

Scleral fragility, increasing the risk for rupture of the white globe of the eye
Microcornea,
Near-sightedness (myopia)
Glaucoma

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Retinal detachment, flashes and floaters

Kyphoscoliotic EDS can be evident at birth. Newborns may demonstrate severe muscular weakness (hypotonia) or abnormal spinal rotations and curvatures (scoliosis). Despite progressive scoliosis, the survival of patients with Kyphoscoliotic EDS is unaffected. The most severely affected adults may lose the ability to walk by their 20s-30s and it becomes important to watch that their scoliosis does not begin to impede normal breathing patterns.

2.2.7 Brittle cornea syndrome

Brittle cornea syndrome (BCS) is a variant of EDS that also involves the eyes. People with variant risk ruptures to the cornea following minor injuries with scarring, degeneration of the cornea (keratoconus), and protrusion of the cornea (keratoglobus). Patients may have blue sclera.

2.2.8 Spondylodysplastic type

Spondylodysplastic EDS, previously spondylocheirodysplastic type, describes an EDS variant with skeletal dysmorphology. It primarily involves the spine and the hands. Clinical presentation can include:

Stunted growth
Short stature
Protuberant eyes with bluish sclera
Wrinkled skin of the palms
Atrophy of muscles at the base of the thumb (thenar muscles)
Tapering fingers.

2.2.9 Musculocontractural type

Musculocontractural type EDS is characterized by progressive multisystem complications. This subtype is especially associated with:

Developmental delay
Muscular weakness plus hypotonia
Facial and cranial structural defects
Congenital contractures of the fingers
Severe kyphoscoliosis
Muscular hypotonic
Club foot deformity
Ocular problems

2.2.10 Myopathic type

Myopathic EDS is characterized by:

Muscle hypotonia evident at birth with muscles that do not function properly (myopathy)

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Scoliosis
Sensorineural hearing impairment may accompany this condition. It shares many features with the kyphoscoliotic form of EDS.

2.2.11 Periodontal type

Periodontal EDS type (formerly EDS VII) has findings that include disease of the tissues surrounding and supporting the teeth (periodontal disease), potentially resulting in premature tooth loss.

3 Evidence Based Treatments

The treatment or management of EDS will depend on the type diagnosed. It can be debilitating to patients and challenging to manage. Multidisciplinary treatment is required, including mental health support for declining psychological wellbeing. There is very little published evidence on in this area and treatments are often based on consensus, expert opinion and case studies [5]. Some broad options relating to common manifestations will be provided below [2, 4, 5].

3.1 Treatment of manifestations

Physical therapy tailored to the individual
Assistive devices
- Braces to improve joint stability
- Wheelchair or scooter to offload stress on lower-extremity joints
- Suitable mattress to improve sleep quality
Pain medication tailored to symptoms
Appropriate therapy for gastritis/reflux/delayed gastric emptying/irritable bowel syndrome
Psychological and/or pain-oriented counselling.

3.2 Prevention of primary manifestations

Low-resistance exercise to increase both core and extremity muscle tone for improved joint stability; appropriate writing utensils to reduce finger and hand strain.

3.3 Prevention of secondary complications

Calcium, vitamin D, low-impact weight-bearing exercise to maximize bone density.

3.4 Surveillance

Dual-energy X-ray absorptiometry (DEXA) every other year if bone loss is confirmed.

Agents/circumstances to avoid

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High-impact activity increases the risk of acute subluxation/dislocation, chronic pain, and osteoarthritis.

3.5 Genetic counselling

Hypermobile EDS is inherited in an autosomal dominant manner. Most individuals diagnosed with the syndrome have an affected parent. The proportion of cases caused by a de novo pathogenic variant is unknown. Each child of an individual with hypermobile EDS has a 50% chance of inheriting the disorder. Because the gene(s) and pathogenic variant(s) responsible for hypermobile EDS have not been identified, prenatal testing is not possible.

3.6 Surgery

Non-operative treatment should be maximized before surgery is indicated. This is because excessive bleeding after can occur after minor trauma or surgery.

4 Prevalence

The estimated overall prevalence of EDS is 1 in 5000, depending on type (hypermobility type is the most common) [1]. It affects males and females of all racial and ethnic backgrounds equally. Classical-type EDS occurs in 1 in 10,000 to 1 in 20,000 infants [1].

In individuals affected by vascular-type EDS, the average age for arterial rupture is 23 years and the median age of death is 48 years [1].

5 Co-existing Conditions

Multiple EDS website list various coexisting conditions but provide no supporting evidence. These include:

Malfunctioning of the autonomic nervous system
Gut dysmotility
Chronic fatigue
Small fibre neuropathy
Cervico-cranial instability
Sleep disorders

There is evidence to suggest that individuals with EDS are at increased risk of being diagnosed with psychiatric disorders [6]. These risk increases may have a genetic and/or early environmental background [6, 7].

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Individuals with EDS have an overall 4.3x relative risk of being affected by any psychiatric disorder. Some of these include [6]:

Autism spectrum disorder
Bipolar disorder
Attention deficit hyperactivity disorder
Obsessive compulsive disorder
Depression
Attempted suicide
Suicide
Schizophrenia

A population based cohort study from Denmark is the first and only study to investigate comorbidities in patient with EDS [8]. This study found that the most common in Danish patients were:

Gastrointestinal functional disorders
Hernias
Asthma
Pneumonia
Osteoporosis.

Other conditions such as epilepsy [9], migraine headache [9], cerebrovascular disease [10], postural orthostatic tachycardia syndrome [11], fibromyalgia [12] and diverticular diseases [12] have also been associated with EDS.

6 List of possible experts in Australia

A healthcare professional’s directory is provided by the Ehlers-Danlos Society. This includes medical doctors, physiotherapists, occupational therapists, podiatrists and dentists. Below are a selection of medical professionals.

Raj Anand, MBBS, FRACP (General Medicine/ Rheumatology) FFPMANZCA
Rheumatology, Pain Medicine

Eastern Suburbs Pain Clinic
Specialist Medical Randwick
Barker Street
Suite 20, Level 7
Prince of Wales Private Hospital
NSW Randwick
0061 2 9650 4988
reception@pwphealth.com.au

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Felicity Collins, MBBS
Clinical Genetics; Paediatrics

Clinical genetics Unit, Royal Prince Alfred Hospital
Missenden Rd, Camperdown
Sydney, NSW 2050
+612-95155080
felicity.collins@health.nsw.gov.au

Louise Tofts, MBBS, DCH, MSpMed, FRACP, FAFRM
Paediatrics, Physical Medicine and Rehabilitation
Narrabeen Sports Medicine Center
Wakehurst Parkway
Narabeen, NSW 2101
http://narrabeensportsmedicine.com.au/paediatrics/dr-louise-tofts/
+61 2 99711188
admin@narrabeensportsmedicine.com.au

Pavla Walsh, MBBS
FRACP, FFPMANZCA, Grad Dip Paed Rheum
Painless
5/136 Railway St
Cottesloe, WA 6011
1300429411
hello@painless.clinic

7 References

Lawrence EJ. The Clinical Presentation of Ehlers-Danlos Syndrome. Advances in Neonatal Care. 2005;5(6).
National Organisation for Rare Disorders. Ehlers Danlos Syndromes 2017 [Available from: https://rarediseases.org/rare-diseases/ehlers-danlos-syndrome/.
Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics [Internet]. 2017 2017/03/01; 175(1):[8-26 pp.]. Available from: https://doi.org/10.1002/ajmg.c.31552.
Levy HP. Hypermobile Ehlers-Danlos Syndrome: University of Washington, Seattle, Seattle (WA); 1993. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1279.
Shirley ED, DeMaio M, Bodurtha J. Ehlers-Danlos Syndrome in Orthopaedics: Etiology, Diagnosis, and Treatment Implications. Sports Health [Internet]. 2012 2012/09/01; 4(5):[394-403 pp.]. Available from: https://doi.org/10.1177/1941738112452385.
Cederlöf M, Larsson H, Lichtenstein P, Almqvist C, Serlachius E, Ludvigsson JF. Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers–Danlos syndrome or hypermobility syndrome and their siblings. BMC Psychiatry [Internet]. 2016 2016/07/04; 16(1):[207 p.]. Available from: https://doi.org/10.1186/s12888-016-0922-6.

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Sinibaldi L, Ursini G, Castori M. Psychopathological manifestations of joint hypermobility and joint hypermobility syndrome/ Ehlers–Danlos syndrome, hypermobility type: The link between connective tissue and psychological distress revised. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2015;169(1):97-106.
Leganger J, Fonnes S, Kulas Søborg ML, Rosenberg J, Burcharth J. The most common comorbidities in patients with Ehlers-Danlos syndrome: a 15-year nationwide population-based cohort study. Disability and Rehabilitation [Internet]. 2020:[1-5 pp.]. Available from: https://doi.org/10.1080/09638288.2020.1761890.
Castori M, Voermans NC. Neurological manifestations of Ehlers-Danlos syndrome (s): A review. Iranian journal of neurology [Internet]. 2014; 13(4):[190 p.]. Available from: https://www-ncbi-nlm-nih-gov.ez.library.latrobe.edu.au/pmc/articles/PMC4300794/.
Kim ST, Cloft H, Flemming KD, Kallmes DF, Lanzino G, Brinjikji W. Increased Prevalence of Cerebrovascular Disease in Hospitalized Patients with Ehlers–Danlos Syndrome. Journal of Stroke and Cerebrovascular Diseases [Internet]. 2017 2017/08/01/; 26(8):[1678-82 pp.]. Available from: https://www.sciencedirect.com/science/article/pii/S1052305717301301.
Sobey G. Ehlers–Danlos syndrome: how to diagnose and when to perform genetic tests. Archives of Disease in Childhood [Internet]. 2015; 100(1):[57 p.]. Available from: http://adc.bmj.com/content/100/1/57.abstract.
Nelson AD, Mouchli MA, Valentin N, Deyle D, Pichurin P, Acosta A, et al. Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic. Neurogastroenterology & Motility [Internet]. 2015 2015/11/01; 27(11):[1657-66 pp.]. Available from: https://doi.org/10.1111/nmo.12665.

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