A GP guide to hypermobile Ehlers-Danlos syndrome
Need to know:
- The Ehlers-Danlos syndromes (EDS) are a group of 14 heritable connective tissue disorders (HCTDs). Joint hypermobility, skin hyperextensibility and tissue fragility are common across all EDS subtypes.
- Hypermobile EDS (hEDS) is the most common subtype, occurring in up to 1 in 500. A lack of awareness and education about the condition means misdiagnosis and delayed diagnosis are common.
- hEDS is a multisystem condition that can affect all organ systems.
- The symptom burden of hEDS can be significant, causing greatly reduced participation in activities of daily living and decreased quality of life.
- Common comorbidities include postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS), both of which are seen in over 80% of EDS patients.
- Validated clinical diagnostic criteria can be used to support a hEDS diagnosis in general practice.
- Given the complexity of hEDS, most patients will have many different non-GP specialists involved in their care. A GP specialist who is able to provide comprehensive care co-ordination is essential for the multidisciplinary team.
The Ehlers-Danlos syndromes (EDS) are a group of 14 heritable connective tissue disorders (HCTDs).1 Hypermobile Ehlers-Danlos syndrome (hEDS), previously known as type III EDS, is the most common subtype and the focus of this article.2,3
hEDS is the only EDS subtype in which the contributing genetic mutations are not known. Unlike other subtypes, which are monogenic, hEDS is thought to be polygenic, with research continuing to determine the potential causative genetic variants.4
The genetically defined EDS subtypes involve defects in collagen synthesis and connective tissue extracellular matrix integrity.
The diagnosis of these subtypes can be confirmed with genomic testing. However, as all genetic variants of hEDS have not yet been characterised, the diagnosis of this subtype is clinical.
Diagnostic criteria were established in 2017 to aid identification and management of these patients.2,3,5,6
The prevalence of all EDS subtypes combined has historically been reported at around 1 in 5000 individuals globally.2 However, findings from a 2019 national electronic cohort study in Wales indicate that hEDS, the most common subtype, may actually occur in up to 1 in 500 individuals. Further, hEDS is estimated to account for 90% of all EDS diagnoses.2,5,7
A rare disease is considered to be one that impacts fewer than 1 in 2000 people. Even though the more recent data set suggest hEDS is more prevalent than this, it is still perceived by many to be a rare condition.8
Lack of understanding of the impacts of hEDS, its inappropriate perception as a rare disease, and insufficient education being included in healthcare professional training, have contributed to under- and misdiagnosis of affected individuals. In turn, for many, disease management is rarely optimised and opportunities for early intervention not realised.5,9,10
As an additional consideration, up to 20% of the general population are hypermobile, though many will be asymptomatic and not require intervention.11 Those with symptomatic joint hypermobility and associated symptoms that do not meet the 2017 hEDS clinical diagnostic criteria, may meet criteria for a diagnosis of hypermobility spectrum disorder (HSD).
HSD can be as disabling and complex as hEDS, and the management of both is similar. HSD and hEDS may be a continuum of the same condition, and work is currently underway to revise the 2017 criteria.2,11
Practically, these two conditions are often coupled together and referred to as hEDS/HSD. The information presented in this article can be applied to both.
Given the complexity and multisystem nature of hEDS, patient care will often require multiple specialists and allied health care professionals.
The role of the GP in diagnosing and co-ordinating care for those with hEDS is important. Holistic ongoing management that promotes improved quality of life while reducing disability and disease impact is highly achievable in primary care.9,10
hEDS is a clinical diagnosis that can be made in primary care settings using the appropriate internationally recognised diagnostic criteria (see resources). 2,6,10,12,13
Presentation
hEDS is a multisystem condition that can impact the connective tissue of any organ system. Clinical features can include neurological, psychological, immunological, cardiac, respiratory, gastrointestinal, urological, gynaecological, musculoskeletal, gastrointestinal and dermatological manifestations.5,7,9–11,14
Table 1 outlines key features and common comorbidities.
The heterogeneity of symptoms experienced in hEDS, variation in the presentation between individual patients, and fluctuations of individual presentations or symptoms over time, adds to the diagnostic challenge.
Chronic pain and fatigue are two of the most commonly reported symptoms in hEDS.2,5,10,15
| Table 1. Summary of key features/common comorbidities noted in hEDS2,5,7,9–11,13,15–20 | |
| System | Key features/comorbid condition |
| Neurological and spine | Headache/migraine Chiari malformation Basilar invagination Idiopathic intracranial hypertension Myelopathy from spinal cord-associated conditions Cervical instability (craniocervical, atlantoaxial, segmental) Cerebrospinal fluid leaks/spontaneous intracranial hypotension Scoliosis Spondylolisthesis Degenerative disc disease Tethered cord/occult tethered cord Myalgic encephalomyelitis/chronic fatigue syndrome. |
| Psychiatric | Mood disorder Anxiety disorder (largely physiological; eg, associated with POTS) Neurodevelopmental disorders (ADHD, autism) Insomnia Clinician associated traumatisation (trauma from medical misdiagnosis/stigmatisation/invalidation). |
| Immunological | Mast cell activation syndrome Asthma Eczema Hay fever Urticaria/rashes Coeliac disease Food intolerances/allergies Drug allergies. |
| Autonomic/cardiovascular | Autonomic nervous system dysfunction (dysautonomia): • postural orthostatic tachycardia syndrome • inappropriate sinus tachycardia • orthostatic intolerance • orthostatic hypotension • vasovagal syncope. Vascular compression syndromes: • internal jugular vein compression • thoracic outlet syndrome • median arcuate ligament syndrome • superior mesenteric artery syndrome • nutcracker syndrome • May-Thurner syndrome • pelvic congestion syndrome. |
| Gastrointestinal | Gastro-oesophageal reflux disease Eosinophilic oesophagitis GI dysmotility (gastroparesis, oesophageal, colonic) Chronic constipation and/or vomiting Irritable bowel syndrome Visceroptosis Abdominal hernias Rectal prolapse. |
| Urogynaecological | Under/overactive bladder Urinary frequency, urgency, incontinence, retention, UTIs Pelvic floor dysfunction Pelvic organ prolapse Dyspareunia Heavy menstrual bleeding Dysmenorrhoea |
| Musculoskeletal | Joint hypermobility Joint pain, dislocation, subluxation, instability/altered mechanics Osteoarthritis TMJ dysfunction. |
| Dermatological | Potential skin characteristics include: • soft/silky/velvety to touch • mild transparency (visibility of veins) • mild skin fragility prone to bruising/injury • slow wound healing • atrophic scars (mildly stretched, sunken) • striae atrophicae (stretch marks) Fascial fragility may cause spontaneous CSF leak, pelvic organ prolapse and hernias. |
| Pain | Acute and/or chronic nociceptive, neuropathic and nociplastic pain. Many potential sources, for example: • acute or chronic nociceptive pain from joint injury, dislocation/subluxation, degenerative disease, muscle spasm • neuropathic pain from nerve injury or entrapment and neurovascular compression syndromes • nociplastic pain/central sensitisation with conditions such as fibromyalgia and complex regional pain syndrome. |
Diagnosis
If any ‘red flag’ signs or symptoms are present (see box 1) referral for further, and likely, genomic evaluation is warranted.
| Box 1. ‘Red flag’ features warranting genetics referral for evaluation for alternative HCTD2,12,21 |
| Personal or family history of: • Congenital/musculoskeletal abnormalities: — Severe scoliosis/progressive or congenital kyphoscoliosis — Hip dysplasia — Talipes equinovarus — Disproportionate short stature — Low trauma and/or multiple fractures — Progressive or congenital contractures — Muscle disease or wasting • Ophthalmic: — Early onset marked short-sightedness — Brittle cornea — Retinal detachment — Lens dislocation • Dental: — Severe gum disease • Cardiovascular: — Vascular aneurysm/dissection — Heart attack under 60 years — Organ rupture • Respiratory: — Recurrent pneumothorax • Dermatological: — Very stretchy skin: • >3cm on neck, elbow, knee • >1.5cm back of hand • >1cm palm — Thin translucent skin — Molluscoid pseudotumours — Significantly stretched scars Family history of: • Sudden unexplained death |
Ideally refer to a public hospital genetics clinic, private geneticist and/or other appropriately qualified specialist. The GP specialist may need to research to identify a local clinician who has adequate knowledge of HCTDs.
After a comprehensive history and examination, and having satisfactorily excluded any ‘red flag’ features that may indicate an alternative HCTD diagnosis, a GP specialist can assess for a clinical diagnosis of hEDS using the 2017 hEDS diagnostic criteria.12
There are three components that must all be satisfied for a clinical diagnosis of hEDS to be made. These are summarised in box 2.2,6,12
| Box 2. Essential criteria for clinical diagnosis of hEDS |
Criterion 1: Generalised joint hypermobility (GJH) present Using the Beighton score with different cut-off scores established for different stages of life: prepubescent children, adults to age 50, and adults aged over 50 years. Historical assessment of hypermobility can be used where the cut-off score is one point below age and sex Beighton score cut-off. Criterion 2: Two of the following features must be present A) Any five of the following: unusually soft/velvety skin, mild skin hyperextensibility, unexplained striae distensae or rubae, bilateral heel piezogenic papules, recurrent or multiple abdominal hernia/s, atrophic scarring, unexplained pelvic/rectal prolapse, dental crowding and high or narrow palate (including historical, ask about braces/dental work), arachnodactyly, arm span to height ratio ≥1.05, mitral valve prolapse, aortic root dilation. B) Positive family history of hEDS in any first-degree relative. C) At least one of the following: a) Chronic musculoskeletal pain (pain daily for ≥3 months) in two or more limbs b) Widespread chronic pain (≥3 months) c) Recurrent joint dislocation or frank instability, without trauma Criteria 3: All prerequisites must be met A) Absence of unusual skin fragility (suggestive of alternate EDS subtype) B) Exclusion/identification of acquired CTDs and autoimmune rheumatologic conditions. Additional diagnosis of hEDS in patients who also have acquired connective tissue disorder (eg, lupus, rheumatoid arthritis) requires Criterion 2, features A and B, to be present. In these patients, Criterion 2C cannot be used to make a diagnosis. C) Exclusion of alternative diagnoses that may include hypermobility (due to hypotonia and/or connective tissue laxity) such as neuromuscular disorders, other HCTDs or skeletal dysplasias. Features of these alternative diagnoses are included as ‘red flags’ in box 1. |
Management
A validated instrument, the Spider Questionnaire, has been developed to rank an individual’s hEDS symptoms to determine which are having the most profound impacts (see resources).
The results can aid development of an individualised management plan, with the patient focusing on the most significant impacts, and with engagement of an appropriate multidisciplinary team.7,22 This may include physiotherapists, exercise physiologists, dietitians, occupational therapists, psychologists, pain specialists, neurologists, surgeons, rheumatologists and/or immunologists.
A knowledgeable GP specialist may manage most medical needs (from diagnosis through to management); however, allied health input is essential.
Symptom control and optimisation of comorbid conditions are the mainstay of management in hEDS. These include measures to address dysautonomia, mast cell activation syndrome (MCAS), and associated presentations such as migraine and chronic pain, along with planning for acute pain and symptom flares.
A stepwise approach to pain management is required, taking into account the type, duration and severity of the pain. Pharmacological interventions may range from the use of simple analgesics like paracetamol on an as-needed basis, through to initiation of adjuvants such as low-dose naltrexone, medicinal cannabis, gabapentinoids, or low-dose tricyclic antidepressants.23–25
Avoidance of long-term opioids is recommended. Note that for those with hEDS, both acute and chronic pain may require simultaneous management. It is also important to note that treating comorbid postural orthostatic tachycardia syndrome (POTS) and MCAS, as well as appropriate physical therapies and other multidisciplinary pain management, will usually significantly reduce pain and the need for pharmacological management.
Management of MCAS and POTS may include identifying and avoiding personal triggers, improving stress management and nervous system regulation, optimising diet, nutrition and gut microbiome, correcting micronutrient deficiencies, and pharmacotherapy.
First-line pharmacotherapy for MCAS includes starting H1 and H2 antihistamines, such as fexofenadine 180mg twice daily and PRN, and famotidine 40mg twice daily. Note that higher doses are required for MCAS management than for other conditions, and often individuals will find that one particular H1 antihistamine works better than others, so a trial of multiple agents is recommended to find the most appropriate for the individual.
There are many other mast cell targeted medications, and often multiple will be needed. These may include montelukast, low-dose naltrexone and/or compounded mast cell stabilisers (ketotifen, sodium cromolyn).26,27
Pharmacological management of POTS can include medications that address tachycardia, such as ivabradine or propranolol; midodrine, which improves peripheral vasoconstriction; and/or fludrocortisone, which targets fluid volume retention. Note that treating MCAS adequately will often reduce symptoms of POTS and the need for POTS-directed pharmacotherapy.26-28
Chronic disease management, and mental health treatment plans (if relevant), should form part of the routine care co-ordination performed by the GP for their patients with hEDS, along with patient education and connection to formal patient advocacy groups (see resources).
Assistance with access to NDIS and disability support services, where applicable, can be a positive outcome of a strong therapeutic GP relationship for those with hEDS.
Recent focused evidence-based clinical care guidelines have been published for the management of childbearing with hEDS, and for the diagnosis of paediatric joint hypermobility.29,30 These should be considered and implemented as appropriate for these specific subgroups of hEDS patients.
Reduced symptom burden and effective management of comorbid conditions such as POTS and MCAS can lead to improved outcomes for any non-pharmacological interventions used such as physiotherapy. This demonstrates the importance of using prescribed pharmacologicals and non-pharmacological strategies alongside each other.17
Could it be hEDS?
The phrase ‘if you can’t connect the issues, think connective tissues’ is an unattributed, commonly used phrase within the world of expert hEDS clinicians and researchers globally. It neatly emphasises not only the spectrum of potential symptoms for those with hEDS, but also the host of comorbid conditions that can, and likely will be, present in these patients.
A recent survey found the median age at initial symptom onset in those with hEDS is 10 years. Yet on average, it took another 10 years for individuals to receive a diagnosis of hEDS. This extended time to diagnosis has been termed ‘the diagnostic odyssey’.31
An Australian survey of 152 women with hEDS noted a delay of 15 years from initial presentation to diagnosis.10 This further highlights the importance and need for medical education on hEDS and HCTDs more broadly in the Australian context.10,15,31
There is great value in diagnosing hEDS for both the patient and the diagnosing clinician.
It is a complex, chronic and debilitating syndrome, and diagnosis can lead to care that is more co-
ordinated and comprehensive, allowing better health outcomes and increased accessibility to assistive and supportive services.
Reducing the ‘odyssey’ means the potential for much greater and active participation in all domains of life for people living with the condition.
Dr Megan Thomas is a GP and a founding director of Connected Health Alliance, a not-for-profit interdisciplinary clinic specialising in EDS and related conditions.
Janna Linke is a pharmacist and founding director of Connective Tissue Disorders Network Australia (CTDNA).
- References on request from Dr Kate Kelso.
