UNDERSTANDING HYPERMOBILE EHLERS-DANLOS SYNDROME & HYPERMOBILITY SPECTRUM DISORDER
The thirteen types of Ehlers-Danlos syndrome
Although this site relates to the hypermobile type of Ehlers-Danlos syndrome, it is rare for a case to fit neatly in a single category and crossover symptoms between different types often occur. Therefore, for information purposes, each type of Ehlers-Danlos syndrome is listed in detail below:
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Features, causes and diagnostic criteria
Of the thirteen types, the four main types of EDS are:
Hypermobile EDS (hEDS)
Prevalence: Although official figures still state the prevalence of hypermobile Ehlers-Danlos syndrome in the population as being around 1 in 5000 people, it is generally acknowledged that the actual prevalence is far higher. A study, published in November 2019, looked at patient records from healthcare service databases in Wales over the 27 years leading up to 2017. The study reports that either the diagnosis Ehlers-Danlos syndrome (EDS) or joint hypermobility syndrome (JHS) was found in the healthcare General Practice or Hospital records of around 1 in 500 people in Wales (Demmler J. et al. 2019).
The report, published in the British Medical Journal, concludes that EDS/HSD are not rare conditions [although genuinely rare sub-types of EDS certainly exist - see below for some examples].
Note for Clinicians:
The information provided to researchers:
i) does not appear to have allowed the authors to fully break down the types of EDS listed in the patient records,
iii) does not appear to have allowed the authors to search for and use only the most up-to-date EDS terminology (as laid out by Castori M. et al and Tinkle B. et al 2017) because the data collection period spanned the 27 years leading up to 2017.
Some will, undoubtably, also question the seeming starting point assumption that hEDS and HSD in general are basically indistinguishable and thus can be counted within the population as the same thing, but this important research still contributes valuable and much-needed evidence to the debate about whether hEDS and HSD are rare conditions or not and seems to align well with anecdotal evidence and the experience/opinion of many patients and EDS charities who maintain that these disorders are much more common than previously thought. By collecting information on the medical diagnostic codings and prescription codes listed on the records of patients, the study also provides data that reinforces the opinion/building evidence that hEDS and HSD are debilitating, multi-systemic syndromes not just musculoskeletal as many physicians see it. The codings for these patients seem to align with conditions associated with EDS/JHS in literature, including (but not limited to) pain, fatigue, cardiovascular, gastrointestinal disorders. and gynaecological disorders, dysautonomia, mast cell activation as well as urinary tract infections.
What can certainly be taken from the report is that many more people than previously realised are suffering from symptomatic generalised joint hypermobility and its associated multi-systemic features, by whatever definition.
To view this paper by Demmler et al, please click here.
To view the concerns raised about this research by Hakim et al, please click here.
To view Demmler et al's the reply to concerns raised by Hakim et al, please click here and scroll down.
People with hEDS may have:
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Hypermobility of the joints (loose, unstable joints that dislocate easily)
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Skin signs - stretch marks, hyperextensibility, atrophic scarring, bilateral piezogenic papules of the heel.
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Pelvic floor - Pelvic floor, rectal, and/or uterine prolapse in children, men or nulliparous women without a history of morbid obesity or other known predisposing medical condition.
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Dental crowding or narrow palette.
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Arachnodactyly - as defined by the Steinberg signs and Walker signs (tests is used in clinical evaluation).
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Arm span to height ratio equal to or greater than 1.05.
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Mitral valve prolapse.
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Aortic root dilation.
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Musculoskeletal trauma / soft tissue trauma (macrotraumas such as dislocations, subluxations; damage to ligaments, tendons and muscles; loss of joint function; microtraumas too small to be noticed as they happen).
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Disturbed proprioception.
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Other musculoskeletal traits such as flat feet, misaligned bones in the elbow or big toes, mild to moderate scoliosis, kyphosis, upper spine lordosis.
(Ref: Malfait et al 2017, 4) & 5)Ehlers-Danlos Society - 2017, Hakim A.J 2017c, Smith C. 2017)
Comorbidities which may be associated with hEDS (this list is not exhaustive)
For some, these conditions may be more debilitating than the joint symptoms / musculoskeletal symptoms. They often impair functionality and quality of life, and should always be determined during clinical encounters, and treated (Malfait F. et al 2017).
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Persistent fatigue.
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Pain (acute, chronic, neuropathic, myofascial).
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Cardiovascular autonomic dysfunction - including postural orthostatic tachycardia syndrome.
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Functional gastrointestinal disorders.
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Sleep disturbance.
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Mechanical and neuropathic bowel dysfunction (e.g. hernia, reflux sluggish bowel and constipation).
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Chronic bowel inflammation (inc. mast cell activation).
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Chiari type 1 malformation.
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Tethered cord syndrome.
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Craniocervical instability.
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Anxiety disorders.
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Depression.
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Myopia
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Astigmatism.
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Poor response to anaesthetic.
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Pelvic floor weakness.
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Chronic bladder inflammation (inc. mast cell activation.
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Earlier than ‘normal’ onset of osteoarthritis.
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Influence of progesterone - worsening musculoskeletal symptoms.
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Heavy and painful menstrual cycle.
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Musculoskeletal and pelvic complications in pregnancy\
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Allergies/mast cell activation.
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Resistance to local anaesthetic
(Ref: Malfait et al 2017, 4) & 5)Ehlers-Danlos Society - 2017, Hakim A.J 2017c, Smith C. 2017)
Causes:
As yet, there are no genetic tests to confirm whether someone has hEDS.
Clinical diagnosis, including a physical examination (to look for musculoskeletal and faulty connective tissue signs and symptoms, as well as the individual's medical history and any family history of the condition) is required.
With regard to comorbidities (see list above) - although their ‘significant association’ is recognised in the EDS international classification papers (which are to be reviewed every two years and updated where necessary), more funding and research is urgently required in order to evidence beyond doubt the multi-system manifestations that experts are recognising daily in their patient clinics i.e. there is currently a significant difference between what we ‘know’ and what can actually be proved. Evidence is mounting, however, and several 'comorbidities' such as functional gastrointestinal disorders,
cardiovascular autonomic dysfunction (including postural tachycardia syndrome), sleep disturbance (including sleep apnoea), and anxiety may well be formally recognised in coming years.
The diagnostic criteria for hypermobile EDS:
The diagnostic criteria for hypermobile EDS can be found by clicking here
Classical EDS
Classical EDS (cEDS) is less common than hypermobile EDS and tends to affect the skin more.
People with cEDS may have:
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joint hypermobility
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loose, unstable joints that dislocate easily
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stretchy skin
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fragile skin that can split easily, especially over the forehead, knees, shins and elbows
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smooth, velvety skin that bruises easily
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wounds that are slow to heal and leave wide scars
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hernias, organ prolapse and cervical insufficiency
(Ref: nhs.uk 2019)
The diagnostic criteria for classical EDS:
NB/ Minimal clinical standards suggesting cEDS are the first major criterion plus either the second major criterion or at least three minor criteria.
Major criteria are:
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Skin hyperextensibility and atrophic scarring; and
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Generalised joint hypermobility (GJH).
The are nine minor criteria:
(1) Easy bruising.
(2) Soft, doughy skin.
(3) Skin fragility (or traumatic splitting).
(4) Molluscoid pseudotumours.
(5) Subcutaneous spheroids.
(6) Hernia (or history thereof).
(7) Epicanthal folds.
(8) Complications of joint hypermobility (e.g., sprains, dislocation/subluxation, pain, pes planus).
(9) Family history of a first degree relative who meets clinical criteria.
A final diagnosis requires confirmation by molecular testing (see below).
Causes:
More than 90% of those with cEDS have a heterozygous mutation in one of the genes encoding type V collagen (COL5A1 and COL5A2). Rarely, specific mutations in the genes encoding type I collagen can be associated with the characteristics of cEDS. Classical EDS is inherited in the autosomal dominant pattern.
Additional notes:
Skin is considered to be hyperextensible if it can be stretched more than:
1.5 cm on the front of the forearms and 1.5 cm on the top of the hands;
3 cm on the neck, elbow and knees;
1 cm on the palm of the hand.
Abnormal scarring can range in severity. Most with cEDS have extensive atrophic scars at a number of sites. A minority are more mildly affected. The relevance of surgical scars should be considered with caution in classical EDS, they can appear normal in patients with classical EDS if well managed. Atrophic surgical scars can be found in the general population due to mechanical factors and site of the incision.
Joint hypermobility is evaluated according to the Beighton score; a Beighton score of >5 is considered positive for the presence of generalized joint hypermobility. Since joint hypermobility decreases with age, patients with a Beighton score <5/9 may be considered positive based on their historical observations.
Vascular EDS
Vascular EDS (vEDS) is a rare type of EDS and is often considered to be the most serious.
It affects the blood vessels and internal organs, which can cause them to split open and lead to life-threatening bleeding.
People with vEDS may have:
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skin that bruises very easily
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thin skin with visible small blood vessels, particularly on the upper chest and legs
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fragile blood vessels that can bulge or tear, resulting in serious internal bleeding
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a risk of organ problems, such as the bowel tearing, the womb tearing (in late pregnancy) and partial collapse of the lung
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hypermobile fingers and toes, unusual facial features (such as a thin nose and lips, large eyes and small earlobes), varicose veins and delayed wound healing.
(Ref: nhs.uk 2019)
The diagnostic criteria for vascular EDS:
Major criteria are:
Family history of vEDS with 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 (CCSF) formation in the absence of trauma.
There are twelve minor criteria. Minimal clinical standards suggesting vEDS diagnostic studies should be performed are: a family history of the disorder, arterial rupture or dissection in individuals less than 40 years of age; unexplained sigmoid colon rupture: or spontaneous pneumothorax in the presence of other features consistent with vEDS. Testing for vEDS should also be considered in the presence of a combination of the other “minor” criteria.
A final diagnosis requires confirmation by molecular testing.
Causes:
Patients with vEDS typically have a heterozygous mutation in the COL3A1 gene, with the rare exception of specific heterozygous arginine-to-cysteine substitution mutations in COL1A1 that are also associated with vascular fragility and mimic COL3A1-vEDS. In very rare instances, biallelic pathogenic variants in COL3A1 may be identified. Vascular EDS is inherited in the autosomal dominant pattern.
Kyphoscoliotic EDS
Kyphoscoliotic EDS (kEDS) is rare.
People with kEDS may have:
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curvature of the spine – this starts in early childhood and often gets worse in the teenage years
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joint hypermobility
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loose, unstable joints that dislocate easily
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weak muscle tone from childhood (hypotonia) – this may cause a delay in sitting and walking, or difficulty walking if symptoms get worse
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fragile eyes that can easily be damaged
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soft, velvety skin that is stretchy, bruises easily and scars
(Ref: nhs.uk 2019)
The diagnostic criteria for Kyphoscoliotic EDS:
Major criteria are:
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Congenital muscle hypotonia;
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Congenital or early onset kyphoscoliosis (progressive or non-progressive); and
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GJH with dislocations/subluxations (shoulders, hips and knees in particular).
There are ten minor criteria, as well as gene-specific minor criteria (four for PLOD1 and four for FKBP14). Minimal criteria suggestive for kEDS are 1 and 2 of the major criteria—congenital muscle hypotonia and congential/early onset kyphoscoliosis—plus either: major criterion 3, or three minor criteria (either general of gene-specific).
A final diagnosis requires confirmation by testing (see below).
Causes:
The majority of patients with kEDS harbor biallelic mutations in PLOD1; recently, biallelic mutations have been identified in FKBP14 in patients displaying a phenotype that clinically largely overlaps with kEDS-PLOD1. Laboratory confirmation should start with a urine test using high-performance liquid chromatography (to evaluate the ratio of lysyl-pyridinoline to hydroxylysyl-pyridinoline crosslinks; a normal ratio is ~0.2, whereas kEDS-PLOD1 range is 2-9). This method is fast and cost-effective and it can also be used to determine the pathogenic status of a variant of uncertain significance. Molecular analysis can follow if the urine test is normal. Whereas absence of an abnormal urinary LP/HP ratio excludes the diagnosis of kEDS-PLOD1, absence of the confirmatory genetic findings does not exclude the diagnosis of kEDS, as other yet-to-be-discovered genes may be associated with this phenotype; however, alternative diagnoses should be considered in the absence of PLOD1 or FKBP14 mutations. Kyphoscoliotic EDS is inherited in the autosomal recessive pattern.
Further information
An full overview of the main features, causes and diagnostic criteria for each of the above types of Ehlers-Danlos syndrome can be found at (in alphabetical order): Ehlers-Danlos Society and Ehlers-Danlos Support UK. and the Hypermobility Syndromes Association
References:
For references and information sources used within this site, please see 'References' page, under 'Resources' on the main menu.
Copyright:
Content within this website and the individual contributions contained in it are protected under copyright by the author and publisher (other than as may be noted herein) - © Understanding Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder. by C. Smith 2017. Images bearing 'redcliffhousepublications.co.uk' are designed and owned by the publisher and subject to copyright, all rights reserved.