PART FOUR: SYMPTOMS AND DIAGNOSIS

8.0 What are the Symptoms?

General symptoms of EDS can include (Krahe, 2018):

• Joints:
  • Joint hypermobility;
  • Loose/unstable joints which are prone to frequent dislocations and/or subluxations;
  • Joint pain;
  • Hyperextensible joints (i.e. they move beyond the joint’s normal range); and
  • Early onset of osteoarthritis.
• Skin:
  • Soft velvety-like skin;
  • Variable skin hyper-extensibility;
  • Fragile skin that tears or bruises easily (bruising may be severe);
  • Severe scarring;
  • Slow and poor wound healing; and
  • Development of molluscoid pseudo tumours (fleshy lesions associated with scars over pressure areas).
• Miscellaneous/Less Common:
  • Chronic, early onset, debilitating musculoskeletal pain (usually associated with hypermobility EDS);
  • Arterial/intestinal/uterine fragility or rupture (usually associated with vascular EDS);
  • Scoliosis at birth and scleral fragility (associated with kyphoscoliosis EDS);
  • Poor muscle tone (associated with arthrochalasia EDS);
  • Mitral valve prolapse; and
  • Gum disease.

Some EDS have specific symptoms as well as the above general symptoms, for example vascular EDS:

• Easy bruising is most often noticed in childhood, often accompanied by visibility of blood vessels through strikingly translucent skin.
• Additional features can include:
  • Unusual bruising without identified cause;
  • Premature aging of hands and feet;
  • Early onset varicose veins; and
  • Distinguishing facial features, including prominent eyes.

It is important to note that not all hyperflexible athletes have a connective tissue disorder and not all individuals with a connective tissue disorder are pathologically flexible (Lavallee, 2015).

9.0 How are Ehlers-Danlos Syndromes Diagnosed?

“The median time from symptom onset to seeking a GP opinion is 2 years and the median time to diagnosis 10 years1. If we make an early diagnosis and manage the conditions appropriately, there may be potential to reduce long term disability which can occur from EDS.” (RCGP, 2019).

The Royal College of General Practitioners (RCGP) advises general practitioners (GP’s) to utilise the JUST GAPE model if they suspect EDS:

• Joints (and U/Other Soft Tissues).
• Gut.
• Allergy/Atopy/Autoimmune.
• Postural symptoms.
• Exhaustion.

The RCGP also uses 5 questions (not validated but planned) to aid in a diagnosis (RCGP, 2019).

Although a GP or physiotherapist can diagnose EDS, those suspected of EDS may be referred by their GP to a specialist doctor such as a geneticist or rheumatologist. Although the RCGP (2019) states:

“Many hypermobile patients will be managed, at least for the majority of their lives, solely within Primary Care. There may not be much advantage to your patient from seeing a rheumatologist who does not have a special interest in hypermobility, certainly not simply for confirmation of a hEDS or HSD diagnosis. However, there are certain situations where a referral may be advisable.”

You can read the RCGP Ehlers-Danlos Syndromes Toolkit here.

A geneticist can give a definitive diagnosis of EDS, except for hEDS, or one of the more than 200 other heritable connective tissue disorders, through molecular testing. A rheumatologist may be able to perform tests which elucidate associated conditions (Section 10 below).

To determine a diagnosis, and the sub-type of EDS, there are several major and minor criteria to consider (Table 4 below).

The pathway to a general diagnosis of EDS may vary slightly depending on whether you are provisionally diagnosed by a doctor or physiotherapist – In some cases, your physiotherapist may suspect EDS and refer you to your GP, and in other cases the GP may diagnose first and refer you to a physiotherapist as part of your treatment – but usually consists of:

• Step 1: Examination by a medical professional:
  • Physical testing:
    • Using the Beighton Scale (Section 4.4) to assess how mobile your joints are.
    • A search for:
      • Abnormal scarring;
      • Testing your skin to determine what it feels like; and
      • How much it stretches.
    • Musculoskeletal, cardiovascular, gastrointestinal, skin, and oral/dental manifestations.
    • Baseline echocardiogram to evaluate aortic root diameter, as adjusted for age and body surface area (Campens et al., 2014). Significant aortic enlargement and/or other cardiac abnormalities should prompt consideration of alternative diagnoses.
    • Identify any co-existing issues such as coeliac disease or inflammatory bowel syndrome.
    • For those with significant pain and/or fatigue, screening for and correction of other potential causes, including (but not limited to) vitamin D deficiency, vitamin B12 deficiency, folate deficiency, iron deficiency, coeliac disease, and/or hypothyroidism.
    • Any additional test your medical professional deems are necessary (including but not limited to):
      • Tilt-table test, if appropriate, to help confirm postural orthostatic tachycardia and/or neutrally mediated hypotension.
      • X-ray spine.
      • Gastrointestinal imaging and endoscopy.
  • Medical history:
    • Your medical history to look for conditions and problems associated with EDS; and
    • A discussion of your family to help determine if the EDS was inherited.
• Step 2: Provisional Diagnosis:
  • Sub-type is given by matching major and then minor symptoms.
  • There can be substantial symptom overlap between the various sub-types.
• Step 3: Examination by a physiotherapist:
  • Subjective assessment during the initial appointment, which is a conversation to collect as much information (subjective history) as possible about the individual and their problems (Parry, 2017).
  • This information is used to determine what physical and functional difficulties you may have.
  • Objective assessment, or physical assessment, is where the physiotherapist will actually exam you and may include, for example, posture, strength, stability/proprioception, gait/mobility, and range of movement.
  • The physiotherapist will now be able to develop a care/treatment plan tailored to you.
• Step 4: Definitive Diagnosis:
  • Requires confirmation by molecular testing to identify the responsible variant of the gene affected in each sub-type.
    • Concurrent single-gene testing which may include sequence analysis, serial gene analysis, and/or gene-targeted deletion/duplication analysis.
    • Multi-gene panel which may include genes not associated with the condition.
    • Comprehensive genomic testing including exome sequencing and genome sequencing.
  • The genetic basis for hypermobile EDS (hEDS) is still unknown, therefore a diagnosis of hEDS is based on clinical criteria and what your medical professional finds during your examination.

Notes:

1. Joint hypermobility is evaluated according to the Beighton Score (Section 4.4).
2. A final diagnosis requires confirmation by molecular testing. 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. cEDS is inherited in the autosomal dominant pattern.
3. clEDS is caused by a complete lack of Tenascin XB (due to biallelic TNXB mutations, that lead to nonsense-mediated mRNA decay, or biallelic deletion of TNXB). TNXB is the only gene associated with clEDS. Classical-like EDS is inherited in the autosomal recessive pattern. Skin hyperextensibility and joint hypermobility are defined as in cEDS.
4. cvEDS is caused by a complete lack of the proa2-chain of type I collagen due to biallelic COL1A2 mutations, that lead to nonsense-mediated mRNA decay. COL1A2 is the only gene associated with cvEDS. cEDS is inherited in the autosomal recessive pattern.
5. 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. vEDS is inherited in the autosomal dominant pattern.
6. The diagnosis of hEDS remains clinical as there is no molecular or genetic cause yet identified.
7. Some of these include sleep disturbance, fatigue, postural orthostatic tachycardia, functional gastrointestinal disorders, dysautonomia, anxiety, and depression. These conditions may be more debilitating than the joint symptoms; they often impair daily life, and they should be considered and treated accordingly.
8. aEDS is caused by heterozygous mutations in either COL1A1 or COL1A2, that cause entire or partial loss of exon 6 of the respective gene. No other genes are associated with aEDS. Absence of a causative mutation in COL1A1 or COL1A2 that leads to complete or partial deletion of the exon 6 of either gene excludes the diagnosis of aEDS. aEDS is inherited in the autosomal dominant pattern.
9. dEDS is caused by biallelic mutations in ADAMTS2. It is the only gene associated with dEDS and is inherited in the autosomal recessive pattern.
10. The majority of patients with kEDS harbour 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 kEDSPLOD1 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. kEDS is inherited in the autosomal recessive pattern.
11. BCS is caused by biallelic mutations in either ZNF469 or PRDM5. At least one family with a clinical BCS phenotype did not harbour mutations in these genes, suggesting that at least one other gene might be associated with BCS. BCS is inherited in the autosomal recessive pattern.
12. spEDS is inherited in the autosomal recessive pattern.
13. mEDS is caused by biallelic mutations in CHST14. A few mutations have been identified in the DSE gene in patients with a similar phenotype. mEDS is inherited in the autosomal recessive pattern.
14. mEDS is caused by heterozygous or biallelic mutations in COL12A1, and the clinical phenotype highly overlaps with collagen type VI-related myopathies. It is currently unknown whether other, yet to be discovered genes, are associated with this phenotype. In case no COL12A1 mutations are identified alternative diagnoses, especially collagen VI-related Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy, should be considered. Myopathic EDS is inherited in either the autosomal dominant or the autosomal recessive pattern.
15. pEDS is caused by heterozygous gain-of-function mutations in C1R or C1S. At present it cannot be stated whether absence of a C1R or C1S mutations excludes the diagnosis because the experience with the molecular diagnosis is limited. pEDS is inherited in the autosomal dominant pattern.

10.0 Differential Diagnosis

Due to the similarity of signs and symptoms of EDS with other diseases, conditions, and disorders, it is important to consider a differential diagnosis. This part of the article outlines some of these.

All sub-types of EDS share some degree of joint laxity and skin/soft tissue manifestations. However, certain other forms of EDS are distinguished by additional connective tissue manifestations (Malfait et al., 2017).

It is important to note that joint laxity is a non-specific manifestation of dozens of other disorders and syndromes. Functionally, joint hypermobility may be the result of:

• Ligamentous laxity (as in the heritable disorders of connective tissue and skeletal dysplasias); or
• Hypotonia (as in mitochondrial diseases and other neuromuscular conditions).

It can be difficult to distinguish between these mechanisms of pathology, especially in adults. Castori and colleagues (2017) suggest that when there is symptomatic joint hypermobility and no other specific diagnosis can be established, it is reasonable to diagnose hypermobility spectrum disorder.

10.1 Hypermobility Spectrum Disorders

Hypermobility spectrum disorders (HSD) (Section 4.0) are a group of conditions related to joint hypermobility.

HSD are intended to be diagnosed after all other possible conditions are excluded, such as any of the EDS, including hEDS. The 2017 hEDS criteria established serious consideration of joint hypermobility with all related symptoms and conditions, with hEDS at one end of the spectrum.

Similar to hEDS, HSD can have significant effects on an individual’s health and can be equal in severity – and both require similar management, validation, and care.

The essential difference between HSD and hEDS lies in the stricter criteria for hEDS compared to the HSD and reflects the more likely hereditary and/or systemic nature of hEDS compared to HSD. The term HSD relates, in fact, to a wide range of musculoskeletal manifestations that can be considered “secondary to” the underlying joint hypermobility.

Although hEDS is the most common form of EDS, other sub-types of EDS should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation. Clinical overlap is seen with all other EDS sub-types.

10.2 Genetically Related (Allelic) Disorders

Genetically related, or allelic, disorders to note include (Malfait et al., 2018):

• No other phenotypes are associated with pathogenic variants in COL5A1 or COL5A2.
• The majority of pathogenic variants in COL1A1 are associated with osteogenesis imperfecta (also known as brittle bone disease, a group of genetic disorders that mainly affect the bones. It results in bones that break easily).
• Rarely, specific pathogenic variants in COL1A1 are associated with:
  • Arthrochalasia EDS;
  • EDS/osteogenesis imperfecta overlap phenotypes (Cabral et al 2005); or
  • Autosomal dominant infantile cortical hyperostosis (aka Caffey disease), typically presents between the ages of 6 weeks and 6 months with irritability, swelling, and multiple bone lesions, commonly including mandibular involvement (Guerin et al., 2012).

10.3 Associated Conditions/Disorders: EDS in General

There are multi-systemic disorders that often are part of having an EDS, and more specifically hEDS. While research has shown there is an association between these disorders and EDS, there is not yet proof that they are caused by the genes that result in EDS. Regardless of the relationship, recognition and treatment of these associated conditions is an important part of living with an EDS or HSD.

With this in mind, there are a number of other associated conditions/disorders that should be noted:

• Autonomic Dysfunction:
  • Common in hypermobility-related disorders and includes (Roma et al., 2018; Hauser, 2019):
    • Postural orthostatic tachycardia syndrome (POTS) is a condition in which a change from lying to standing causes an abnormally large increase in heart rate. Diagnosis in adults is based on an increase in heart rate of more than 30 beats per minute within ten minutes of standing up which is accompanied by symptoms. POTS affects many different people, but is most common in girls and women aged 15 to 50. Comorbidities of POTS include (among others): coeliac disease; depression disorders; hEDS; HSD; MCAS; and migraine (Miranda et al., 2018). “One-third of people with POTS have comorbid Ehlers-Danlos syndrome… (Miranda et al., 2018, p.168).
    • Orthostatic intolerance (OI) is the development of symptoms when standing upright which are relieved when reclining. There are many types of orthostatic intolerance. OI can be a subcategory of dysautonomia, a disorder of the autonomic nervous system occurring when an individual stands up.
    • Neurally mediated hypotension (NMH) occurs when there is an abnormal reflex interaction between the heart and the brain, both of which usually are structurally normal. This disorder causes blood pressure to drop after standing for long periods, leading to symptoms such as dizziness, nausea and fainting.
  • May cause:
    • Tachycardia (a common type of heart rhythm disorder (arrhythmia) in which the heart beats faster than normal while at rest).
    • Hypotension (low blood pressure).
    • Gastrointestinal problems.
    • Bladder issues.
    • Sweating too much or too little.
  • Statistics:
    • 49% with hEDS have POTS, 31% have OI, and 20% have normal haemodynamics (blood flow) (Celleti et al., 2017).
    • In hEDS, autonomic dysfunction is classified as: mild (47%); moderate (33%); or severe (3.3%) (De Wandele et al., 2014).
• Chronic Fatigue:
  • Common in hypermobility conditions.
  • Symptoms overlap chronic fatigue syndrome (CFS).
  • Problems that worsen fatigue include:
    • Sleep disorders.
    • Autonomic dysfunction.
    • Chronic and acute pain.
    • Deconditioning.
    • Psychological issues.
    • Nutritional deficiencies.
• Gastrointestinal Disorders:
  • Common in hypermobility conditions:
    • Structural such as hiatal hernias and rectal prolapse.
    • Functional such as irritable bowel syndrome and gastroparesis (a condition in which your stomach cannot empty itself of food in a normal fashion).
    • Added precautions for gastrointestinal procedures may be needed depending on EDS sub-type and the individual.
• Neurological and Spine Issues:
  • Laxity in ligaments caused by EDS can result in one or more of the following:
    • Craniocervical instability (CCI), also known as the Syndrome of Occipitoatlantialaxial Hypermobility, is a structural instability of the craniocervical junction which may lead to a pathological deformation of the brainstem, upper spinal cord, and cerebellum.
    • Chiari malformation is a condition in which brain tissue extends into your spinal canal. It occurs when part of your skull is abnormally small or misshapen, pressing on your brain and forcing it downward.
    • Tethered cord syndrome occurs when tissue attachments limit the movement of the spinal cord within the spinal column. In some cases, it may be the result of improper growth of the neural tube during fetal development, which is closely linked to spina bifida.
    • Early disc damage.
    • Muscle weakness.
    • Migraine
    • Kyphosis is an abnormally excessive convex curvature of the spine (aka hunchback) as it occurs in the thoracic and sacral regions. An abnormal inward concave lordotic curving of the cervical and lumbar regions of the spine is known as lordosis.Motor delay.
    • Unstable vertebrae.
• Pain Management:
  • Chronic and acute pain are common including:
    • Joints.
    • Gastrointestinal system.
    • Temporomandibular joint (TMJ), two joints connecting the jawbone to the skull.
    • Headaches and migraines.
    • Pelvic organs.
    • Other systems and locations.
• Mouth and TMJ Issues:
  • Those with EDS may have issues with their teeth, TMJ, facial tissue and headaches.
• Mast Cell Disorders:
  • Mast cell activation syndrome (MCAS) is commonly seen in those with EDS.
  • Mast cells are allergy cells responsible for immediate allergic reactions. They cause allergic symptoms by releasing products called “mediators” stored inside them or made by them.
  • Management includes identifying triggers and avoiding them as well as using medications to manage mast cells.
• Psychiatric and Psychological Symptoms:
  • Research suggests an association with EDS of:
    • Anxiety.
    • Depression.
    • Neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD).
  • Those with EDS may benefit from:
    • Appropriate medication.
    • Psychotherapy.
    • Physical therapy and other treatment of physical symptoms.
  • These symptoms are the result of having an EDS; EDS are not the result of any of these conditions.

10.4 Associated Conditions/Disorders: hEDS Specific

The following disorders (Table 5), can in general, be easily distinguished from EDS by characteristic features and/or involvement of systems other than the joints and skin, but mild presentations can sometimes be misdiagnosed as hEDS.

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