Demystifying Ehlers Danlos Syndrome

Today 13 subtypes of EDS are recognised. The combined prevalence of all EDS variants is estimated at 1 in 5,000 with the hypermobility variant the most common at approximately 1 in 10,000.2, 3 Given EDS is a collagen disorder, involvement of blood vessels, heart valves, internal organs, bone and even sclerae, may present as childhood bleeding diathesis, varicose veins in early adulthood, aneurysmal rupture, cardiac failure, uterine rupture during pregnancy, gastrointestinal dysmotility and perforation, spontaneous pneumothoraces, severe scoliosis and even ocular complications. Fortunately, these are all rare with most catastrophic outcomes occurring in those with the vascular EDS (vDS) variant.

The Most Common Variants Hypermobile Eds

The diagnosis of hypermobile EDS (hEDS) remains particularly controversial and divisive amongst physicians. It was previously known as EDS type 3 and was historically characterised by frequent dislocations or subluxations of large and small joints alike, along with smooth, soft, velvet like skin with a marked predisposition to easy bruising. There is less of a tendency towards hyper-elasticity of the skin. Some affected individuals tend to report chronic muscular pain, fatigue and often palpitations, dizziness, presyncope and symptoms suggestive of postural orthostatic tachycardia syndrome (POTS).

While hEDS tends to display an autosomal dominant (AD) inheritance pattern there is no known associated monogenic cause. This cohort are hypermobile by definition and therein lies the controversy as 10-30% of the general population meet the required hypermobility Beighton score of 5 or more for diagnosis.5 If this degree of “hypermobility” is coupled with a history of chronic widespread pain and a family history of hEDS, then it becomes all too easy for this diagnostic label to be assigned.

Classical EDS

Classical EDS (cEDS) has historically accounted for 80% of EDS cases reported in the literature.6 It displays AD inheritance pattern with mutations typically affecting the production of type V collagen (COL5A1, COL5A2). These patients display hypermobility with joint dislocations, increased skin elasticity with a soft velvet like quality and a predisposition to atrophic scaring. While cEDS patients may develop hernias, uterine complications, molluscoid pseudotumours (calcified haematomas), spheroids and poor post-surgical incision site healing, life expectancy is still unaffected. In paediatrics, easy bruising, hypotonia and delayed motor developmental milestones with a family history of hypermobility should raise suspicion of this disorder. Despite similarities to the hEDS variant, the distinguishing feature of cEDS is the pronounced skin involvement.

Classical-like EDS (cLEDS) displays an autosomal recessive (AR) pattern with a mutation in the TNXB gene on chromosome 6 causing a tenascin X deficiency. Given the role of tensascin X in the function of healthy type 1 collagen, patients with this mutation also display hypermobility, skin hyperextensibility and easy bruising. The differentiating hallmark in cLEDS as opposed to cEDS is the absence of atrophic papyraceous scars. These patients may also develop mild muscle weakness, atrophy of hand and foot muscles, lower limb oedema and cavitary prolapse.

Vascular EDS

Vascular EDS (vEDS) displays an AD inheritance pattern, and unlike the classical or classical-like variants, it is associated with premature mortality with a historical mean survival of 51 years owing largely to arterial or visceral rupture.7 vEDS occurs due to a mutation affecting type 3 collagen (COL3A1). For every 10 cases of classical EDS, there exists 1 case of vascular EDS in the general population. This makes vEDS is exceptionally rare at approximately 1 case per 200,000 people.

While it displays an AD inheritance pattern, 50% of cases occur as a result of a de novo mutation. Younger individuals are protected from aneurysm formation until the end of puberty when elastin production drops off dramatically. Skin may appear translucent making veins very noticeable. vEDS patients tend to display faster skin aging particularly where skin is thinner over the hands and feet. Significantly, there is no increased skin laxity like in other forms of EDS. Hypermobility is only present in the fingers and there may be a predisposition to easy bruising.

Only 30% of vEDS patients have the classical EDS facies of prominent eyes, thin lips and nose, along with a lean hollowed appearance to the cheeks. The chin may also match the slender facial features, making the appearance of the eyes all the more prominent. As a result, when the classical facial features are absent as in the majority of cases. vEDS may remain undiagnosed in those with de novo mutations until catastrophic acute presentation.

New cases of vEDS in patients in their teens and twenties should be considered in those that develop recurrent spontaneous pneumothoraces, bowel rupture or varicose veins. Ultimately 80% will present before the age of 40 with a vascular event. Commonly aortic aneurysms and carotid-cavernous sinus fistulae develop over time. In the latter such cases, patients may present with progressive swelling, conjunctival injection or haemorrhage, pulsating proptosis of the ocular globe along with 6th nerve palsy, all of which are due to arterialisation of blood flow from the carotid artery into the cavernous sinus and the superior ophthalmic vein. The risk of aortic aneurysmal rupture is also extremely high yet operative intervention has historically conferred a 1 in 3 risk of death within the 2 week post operative period. There is also a high risk of uterine rupture in vEDS with pregnancy associated with a 5% mortality risk to the mother.

The Red Flag Red Eyes of Vascular EDS

This is the case of patient A, a woman in her early 30s who was originally investigated for a collagen disorder in her 20s after severe bleeding and poor wound healing post varicose vein stripping. She looked different to other family members on account of her large eyes, slender facial features and propensity to easy bruising. Ms. A was diagnosed with vascular Ehlers Danlos after specialist review and genetic testing ex domo.

In recent months, Ms. A began to develop a whooshing sound and diplopia with exertional Valsalva while weight training. She presented with progressive swelling, pain and protuberance of the left eye. Examination revealed chemosis, marked conjunctival injection and pulsating proptosis of the left globe with evident mild bilateral 6th nerve palsies. Visual acuity was preserved at 6/5 with normal optic nerve and disc. Neuroimaging with CT intracranial angiogram and MRA demonstrated bilateral carotid-cavernous fistulae with engorgement of both superior ophthalmic veins, left greater than right. Ms. A proceeded to endovascular embolization of the left carotid-cavernous fistula but developed a complete left 6th nerve palsy and a complete left 3rd nerve palsy in the post-operative period. Treatment with high dose dexamethasone was commenced with partial recovery to date.

Many suspected EDS cases referred to tertiary care centres will either be the hEDS variant or simply benign joint hypermobility syndrome (JHS) which most often does not display increased elasticity of the skin. Skin hyperextensibility is defined as a capacity to stretch the skin 3cm at the neck, elbows and knees and 1.5cm at the distal forearm or dorsum of the hand. After hEDS, the most common variants encountered by the adult rheumatologist will be the classical and classical-like variants, followed then by vascular EDS. Everything else is either exceptionally rare or diagnosed in the first 3 years of life on account of known family history, congenital hip dislocations, easy bruising, profound muscle hypotonia and missed motor developmental milestones.

When trying to differentiate between hEDS and JHS, there is undoubtedly a significant overlap of symptomatology with other chronic pain syndromes such as fibromyalgia. Both hEDS and JHS are associated with chronic headaches, fatigue, pain amplification, depression, palpitations and dizziness. So much so that some experts will argue that hEDS and JHS are one and the same, differing only in terms of severity. Indeed, the diagnostic label of hEDS itself remains highly controversial given the highly malleable diagnostic criteria.

After exploring patient and family history, a thorough examination of the integumentary system should be performed assessing skin distensibility over dorsum of hand, elbow, neck and knees making note of both skin quality, translucency, veins and any evident scarring. This should be followed by assessment of hypermobility formally using the Beighton criteria. In small children, motor development should be assessed along with generalised muscle tone. Easy bruising should be investigated with laboratory tests for FBC, coagulation profile and clotting factors to outrule bleeding disorders. Baseline transthoracic echocardiogram should be performed in children under the age of 10.8

If there is a family history of vascular EDS or a history of unexplained recurrent pneumothoraces or bowel perforation in a young patient, then CT of aorta, aortic arch and intracranial angiogram should be performed to outrule arterial aneursyms of the aorta, carotid and vertebral arteries, circle of Willis or the abdominal and renal arterial vasculature. If there is a concern with radiation exposure the corresponding MRA sequences may be requested. Crucially, the rheumatologist should be aware that pneumothoraces and bowel perforation may occur in teenage vascular EDS patients long before arterial aneurysms begin to form as they are generally protected from catastrophic arterial events until elastin production drops off dramatically in the 3rd decade of life.

Most of the time in adult rheumatology, genetic testing will not add much additional benefit given most of the cases encountered will either be the hypermobile variant, for which there is no one gene association, or the classical or classical-like variants which do not affect life expectancy. Rarer forms of EDS arrive with a diagnosis from either family history or genetic testing early in life as an infant. Genetic testing may be useful in the young patient with recurrent pneumothoraces and/or spontaneous bowel perforation without family history of vascular EDS. This may either be confirmatory of vEDS before aneurysms form, or may allay such concerns for the future. Testing for the COL3A1 mutation may also be useful in the middle-aged patient with multiple arterial aneurysms without alternative explanation. Fortunately, EDS genetic panels are becoming more inexpensive over time, but still add little that would change management in most cases seen in the adult rheumatology outpatient setting. Is this really vascular EDS or something else?

Recurrent pneumothoraces, spontaneous bowel rupture, varicose veins with or without atrophic scarring in early adulthood should raise suspicion of cEDS, cLEDS and vEDS. The key distinguishing feature being that patients affected by the vascular variant do not display skin hyperelasticity and are only hypermobile in the fingers. There exists an important differential for the hypermobile patient with evidence of aortic root involvement on echocardiogram that all rheumatologists should be aware of. This differential includes the vascular EDS variant, Marfan syndrome, Loeys-Dietz syndrome (LDS) and Cutis Laxa. Interestingly vEDS, Marfan’s and Loeys-Dietz may all display pectus abnormalities and both vEDS and Marfan’s may display a high arched palate. Marfan’s can be distinguished clinically from vEDS easily by its characteristic phenotype of tall stature, arm span to height ratio, long thin extremities and arachnodactyly, as well as by family history and genetic testing. LDS classically presents with the characteristic triad of bifid uvula or cleft palate, hypertelorism and aortic aneurysm. Importantly, while LDS also displays AD inheritance, 75% of cases arise from de novo mutations. vEDS and LDS can usually be differentiated between by evident increased ocular spacing and abnormalities of the arch of the palate and the uvula. Cutis laxa tends to be detected earlier in life on account of the dramatic lack of elasticity of the skin, though the condition can be acquired either due to certain drug exposures or autoimmune and neoplastic causes. The differentiating clinical finding is the slow manner in which skin distension in these patients returns to its original form.

Lastly, there are also a few important distinctions to make between EDS and Osteogenesis Imperfecta (OI) type 1. While also hypermobile, OI patients tend to experience multiple fractures over the course of their lifetime. Non-deforming OI patients, like vascular EDS, may present with complications of multiple arterial aneurysms. In the absence of genetic testing, OI patients differ insofar as they may also present with blue sclerae, dental issues and sensorineural deafness. Furthermore, while the OI patient may be hypermobile, the vascular EDS patient is not in the general sense save for the fingers.

It is strongly recommended that vEDS patients wear an identifying medical alert bracelet as well as an information card as the morbidity and mortality of the condition are not widely appreciated by all in the medical community. Medical attention should be promptly sought if any unexplained severe pain develops. Sudden onset chest, back or abdominal pain should be considered a medical emergency until proven otherwise as it may indicate dissection or even rupture of aorta or perforation of the bowel or solid organ. As operative intervention is fraught with risk, surgery should only proceed if there is a serious life-threatening event such as arterial rupture or perforation of the bowel or solid organ. Any other intervention should ideally be discussed in detail with careful planning and risk mitigation. Input from vascular, plastics and GI surgical specialties are strongly advised if surgery is elective.

Close control of systolic blood pressure over time is thought to potentially delay or offset aneurysm development and arterial emergencies. The antihypertensive agent of choice is usually a beta-blocker with celiprolol showing some promise in small studies to date.9 Celiprolol is available in Europe but to the best of the authors’ knowledge is still not approved in the US for vEDS, despite being a medication first introduced in the 1980s. Alternatively, atenolol and propranolol may be reasonable choices for beta-blockade. If a second anti-hypertensive is needed, angiotensin receptor blockers (ARBs) are likely the next most beneficial agents to consider. Given the high risk of bowel perforation, vEDS patients may benefit from stool softeners and bulk laxatives rather than stimulant laxatives which may actually increase the risk of perforation.

Mechanistically, inhibition of matrix metalloproteinase activity with tetracyclines remains appealing but there is still a lack of strong real-world evidence demonstrating the delay of aneurysm formation and reduction in mortality. Critically, fluoroquinolone antibiotics should be avoided entirely given their deleterious effect on collagen. The same is true in other connective tissue disorders such as Marfan syndrome and Loeys-Dietz syndrome.

All pregnant women with vEDS should be followed in a high-risk obstetric clinic. Ideally, careful family planning would include genetic counselling and discussion of the very real pregnancy associated mortality risk to the mother. While the risk of uterine rupture confers a 5% risk of death to the expectant mother, 50% of those deaths occur with the first pregnancy. Any potential benefit of scheduled caesarean section remains unclear. In certain parts of the world, pre-implantation genetic diagnosis and the selection of unaffected embryos for implantation is a possibility to ensure an unaffected healthy child.

vEDS patients should avoid contact sports, overhead weight lifting and any activity involving prolonged Valsalva. Light weights, gentle jogging and low impact exercise such as cycling and swimming are all more appropriate ways of maintaining cardiovascular fitness and general health.

Acknowledgements:

Beaumont rheumatology department would like to thank our vascular EDS patient for kindly giving permission to use her case history, imaging and clinical photographs for this review article and other educational purposes.

References available on request