Ehlers-Danlos Syndrome

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Article initiated by:

Alexander Engelmann, MD

All contributors:

Caitlin Makenzie Hackl, Samir Cayenne, Andrew Go Lee, MD, Vatinee Y. Bunya, MD, MSCE, Michael T Yen, MD, Natalie Homer, MD., Alexander Engelmann, MD, Cat Nguyen Burkat, MD FACS, Sanjana Jaiswal

Assigned editor:

Masako Chen, MD, Natalie Homer, MD.

Review:

Assigned status Up to Date

 by Natalie Homer, MD. on July 2, 2024.

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Contributing Editors:	add

Ehlers-Danlos Syndrome is a group of connective tissue disorders that should carry weight for ophthalmologists, especially when planning surgery.

Disease Entity

Ehlers-Danlos Syndrome

Disease

The Ehlers-Danlos Syndromes (EDS) comprise a group of heritable connective tissue disorders, which are commonly characterized by tissue fragility, hypermobility, and hyperextensibility. Many ocular manifestations have been identified. Sporadic cases have been identified in the setting of spontaneous mutation.

The most common subtype is classic Ehlers-Danlos Syndrome (cEDS), accounting for an estimated 90% of cases, which is marked by joint hypermobility.

Prevalence is estimated at 1 in 5000, no sex or ethnic predilections.

General manifestations typically involve ability to bend various joints and stretch the skin to extreme degrees, but beyond this the disease may carry morbidity risks related to joint dislocation, scarring, and fragility of blood vessels and organs, as with vascular type EDS.

It is important to distinguish EDS from other hypermotility syndromes, such as Marfans, cutis laxa, pseudoxanthoma elasticum, and Loeys-Dietz.

Risk Factors

First degree relatives with Ehlers-Danlos.

Etiology

Cause varies according to the specific subtype of EDS, but many genes relating to collagen structure and formation have been identified, mostly involving collagen types I, III, and V.

Several classification structures have been proposed, starting with the Beighton classification (5 subtypes) in 1970, followed by the 11 subtypes in the Berlin classification, then the 6 subtypes identified by Villefranche in 1997. The most recent classification was determined during the Ehlers-Danlos Syndrome International Symposium in 2016, which totals 13 subtypes. There is likely to be overlap between classes.

Pathophysiology

Electron microscopy in EDS reveals disruption of the collagen fibrils, their appearance typically described as “collagen flowers”.

Classical EDS is caused by mutations to COL5A1 and COL5A2, which leads to abnormal fibrillar assembly. Not only is collagen type V abnormal, but type I and III are misassembled as well.

Vascular EDS is caused by mutations to COL3A1.

The TNXB gene (tenascin-X protein), is a non-collagenous protein which has been found to be involved in two subtypes of EDS. Some patients with the classic-like form of EDS have an deletions of TNXB, while some patients with hypermobility type EDS have mutations in TNXB or haplo-insufficiency.

Brittle Cornea Syndrome has been associated with 2 gene mutations, involving ZNF469 and PRMD5. Both seem to be related to the expression of extracellular matrix components.

Kyphoscoliotic EDS was previously termed EDS type VI, ocular type. It is marked by lysine-hydroxylase deficiency (PLOD gene mutation).

Primary prevention

None.

Diagnosis

Clinical diagnostic criteria exist for each subtype, as well as confirmation testing for all subtypes except hypermobility type.

Classical EDS requires presence of skin hyperextensibility as well as atrophic scars and either joint hypermobility or 3 minor criteria.

Brittle cornea syndrome is a very rare form of EDS, characterized by thin corneas with keratoconus or keratoglobus. Diagnosis requires thin corneas with or without rupture plus one other major criterion or 3 minor criteria. Urinary lysyl and hydroxylysl pyridinoline ratio are normal, in comparison with kyphoscoliotic EDS, which has elevated ratios.

Vascular EDS requires family history of vascular EDS, arterial dissection <40 years, unexplained hollow viscous rupture, or spontaneous pneumothorax in setting of other features suggestive of EDS.

There are several joint mobility screening tools, which may be useful.

Beighton Mobility Scoring Scale

A score of 5 or more defines generalized joint hypermobility for both sexes (for hypermobile EDS, age and sex-related cut-off points are used).

Joint	Negative	Unilateral	Bilateral
Passive dorsiflexion of the 5th finger >90 degrees	0	1	2
Passive flexion of the thumbs to the forearms	0	1	2
Hyperextension of the elbows >10 degrees	0	1	2
Hyperextension of the knees >10 degrees	0	1	2
Forward flexion of the trunk with knees fully extended and palms resting on the floor	0	1

A “yes” answer to two or more questions (= positive 5PQ) suggests joint hypermobility with 80–85% sensitivity and 80–90% specificity.

The Five-Point Questionnaire (5PQ)
1. Can you now (or could you ever) place your hands flat on the floor without bending your knees?
2. Can you now (or could you ever) bend your thumb to touch your forearm?
3. As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?
4. As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?
5. Do you consider yourself “double-jointed”?

History

Ocular: strabismus, amblyopia, irregular astigmatism, high refractive error, convergence insufficiency, dry eye, spontaneous eyelid eversion, chronic foreign body sensation, recurrent subconjunctival hemorrhage. Vascular complications from EDS may include cervical artery dissection, presenting as new onset diplopia, blurred vision, transient visual obscurations, nystagmus, Horner syndrome, decreased corneal sensation and visual field defects.

General: multiple fractures, “stretchy skin”, easy bruising, abnormal or atrophic scarring, hyperflexible joints, prolonged recovery from concussion, inguinal hernia, poor exercise tolerance, pain intolerance, psychiatric disturbance.

Symptoms

Dry eye, blurred vision, difficulty focusing at near, binocular diplopia, headaches.

Signs

Myopia (25.3%), thin pachymetry, steep keratometry values, irregular astigmatism, increased applanation-related stromal folds, convergence insufficiency.

Physical examination

Epicanthal folds (18.6%), infraorbital creases (29.3%), hypertelorism (8%), ptosis (32%), strabismus (8%), blue sclerae, early tear break-up time (7%), lenticular changes, corneal thinning. Cases of significant conjunctivochalasis has been reported. Floppy eyelids is very common and hypothesized to result from abnormal heterotypic type I/V collagen interactions and collagen fibrillogenesis. While ectopia lenis is less commonly seen in EDS, than with Marfan Syndrome, it has been reported.

a. epicanthal folds, telecanthus, palpebral ptosis, infraorbital creases and bluish sclerae; b. telecanthus, epicanthal folds, palpebral ptosis, ectropion, and downslanting palpebral fissures; c. synophrys and epicanthal folds; d. blepharochalasis, infraorbital creases, and bluish sclerae; e. blepharochalasis, downslanting palpebral fissures, infraorbital creases, and bluish sclerae; f. telecanthus, blepharochalasis, infraorbital creases, and upslanting palpebral fissures; g. deep-set eyes, blepharochalasis, and bluish sclerae; h. deep-set eyes and bluish sclerae.

Despite being known as the ‘E’ the commonly used mnemonic “PEPSI” for conditions associated with angioid streaks, this association has not been born out in literature since its initial observation.

Examination of the skin may reveal hyperextensibility, thinness, fragility, easy bruising, varicosities, soft/velvety texture, and abnormal scars.

Examination of the joints may reveal hypermobility.

Differential diagnosis

Osteogenesis imperfecta: blue sclerae, multiple fractures, short stature.

Marfan syndrome: ectopia lentis, marfanoid habitus, aortic dilatation/aneurysm.

Loeys-Dietz syndrome: Hypertelorism, aortic root dilatation/dissection, arterial tortuosity, bifid uvula, cleft palate, craniosynostosis, micro-retrognathia, mild myopia, amblyopia, strabismus, blue sclerae, retinal detachment, retinal tortuosity, cataract. Craniofacial abnormalities distinguish Loeys-Dietz Syndrome from EDS.

Stickler syndrome: vitreoretinal abnormalities, cataract, high myopia, sensorineural hearing loss, cleft palate.

Cutis laxa: redundant skin hanging in folds, normal wound healing, absence of skin fragility.

Larsen syndrome: craniofacial dysmorphism, short stature.

Labs/Testing

Given the heritability of EDS and the potential management implications depending on subtype, molecular diagnosis is necessary in all cases. Genetic testing for the various collagen (COL5A1 and COL5A2) and non-collagen mutation, as described above, is advised. Next Generation Sequencing for DNA testing.

In kyphoscoliotic EDS (Villefranche EDS VI, ocular type), lysyl hydroxylase activity can be assessed using a urine assay. Decreased activity least to high deoxypyridinoline:pyridinoline ratio.

Biochemical testing and skin biopsy may be necessary for exploration of the differential.

Management

Multi-disciplinary team with EDS expert. Genetic counseling.

Patients with Ehlers-Danlos Syndrome should receive a complete ophthalmologic exam.

Medical therapy

Patients with symptomatic convergence insufficiency may be offered vergence and accommodative therapies.

Patients should don protective eyewear whenever there is a risk of ocular trauma.

There have not been adequate trials to assess the efficacy of supplements such as chondroitin, coenzyme Q10, ascorbic acid, glucosamine, and pycnogenol. These supplements would not be expected to have great effect, if any.

Advise regarding risk of arterial rupture and bony fracture. Patients with more fragile subtypes of EDS should avoid high impact activity, such as contact sports.

In patients with vascular EDS, take caution when considering anti-coagulation or anti-platelet medications.

Surgery

Surgical repair of the ophthalmic and periorbital malformations related to EDS may be necessary. Extra care should be taken when operating on a patient with EDS, as the skin is more likely to be thin, hyperextensible, and generally prone to easy injury. Sutures may tear the skin and lead to dehiscence or increased scarring if placed under tension. It is important to consider Lange’s skin lines and minimize tension across wounds. Scarring may be worse.

Strabismus surgery may be warranted in patients with qualifying forms of strabismus.

Complications

A survey of patients with a confirmed Ehlers-Danlos syndrome diagnosis who had undergone ocular surgery reported complication rates according to type of surgery:

59% of strabismus cases, 33% of lens/cataract cases, 33% of retina cases, 25% of glaucoma laser cases, 23% of oculoplastics cases, 23% of refractive cases, 0% of cornea cases.

Prognosis

EDS may predispose individuals to a greater risk of open globe with ocular trauma. In kyphoscoliotic EDS, scleral rupture is more common, whereas in brittle cornea syndrome, corneal rupture is more common.

Ocular conditions related to EDS have a better prognosis when diagnosis is made earlier. Surgical outcomes may be more favorable if the diagnosis of EDS is made prior to surgery.

Vascular EDS carries the greatest morbidity and mortality rate, as sudden death tends to occur in 3rd or 4th decade of life due to spontaneous arterial rupture.