Ehlers-Danlos syndrome (EDS) is a group of disorders in which connective tissue becomes fragile due to genetic abnormalities in collagen structural genes or their metabolic enzymes. It is named after Ehlers, who reported skin and joint lesions in 1901, and Danlos, who reported subcutaneous pseudotumors in 1908.
The estimated prevalence is 1 in 5,000. There is no sex or ethnic predilection. In 2017, the International Symposium on Ehlers-Danlos Syndrome established 13 subtypes 1). The major subtypes and associated genes are shown below.
Subtype
Responsible gene
Inheritance pattern
Classic type (cEDS)
COL5A1/A2
AD
Hypermobile type (hEDS)
Unknown
AD
Vascular type (vEDS)
COL3A1
AD
In addition, there are many other subtypes such as brittle cornea syndrome (BCS: ZNF469/PRDM5), kyphoscoliotic type (kEDS: PLOD1), and classic-like type (clEDS: TNXB)1).
It is important to distinguish EDS from Marfan syndrome, osteogenesis imperfecta, cutis laxa, pseudoxanthoma elasticum, and Loeys-Dietz syndrome.
QHow many types of EDS are there?
A
According to the 2017 international classification, EDS is classified into 13 subtypes1). The classic, hypermobile, and vascular types are the major subtypes. Of particular ophthalmological importance are brittle cornea syndrome (BCS) and kyphoscoliotic type (kEDS), which carry risks of corneal rupture and globe rupture, respectively.
Patients may complain of dry eye, decreased vision, difficulty focusing at near, binocular diplopia, and headache. In vascular EDS, transient visual disturbances and Horner syndrome due to carotid artery dissection may present as new-onset visual abnormalities.
Blue sclera: The uvea is visible due to thinning and transparency of the sclera. This is a representative complication along with osteogenesis imperfecta.
Epicanthus: Observed in 18.6% of cases. It may be accompanied by telecanthus (increased intercanthal distance).
Ptosis: Reported in 32% of cases. Floppy eyelid is also frequently observed, and an association with type V collagen abnormality has been suggested2)3).
Corneal thinning: Pachymetry shows thinning, accompanied by steep corneal curvature and irregular astigmatism.
Lens and Posterior Segment Findings
Keratoconus: Characteristic of the BCS type. Keratoconus is widely recognized as a related genetic disorder of EDS4).
High myopia: Observed in 25.3% of cases. Axial myopia is predominant.
Retinal detachment: Commonly associated with the kyphoscoliotic type. It may be accompanied by vitreous liquefaction.
Lens dislocation: Not as common as in Marfan syndrome, but reported.
Infraorbital groove (29.3%), hypertelorism (8%), strabismus (8%), and shortened tear film breakup time (7%) have also been reported. There are case reports of marked conjunctivochalasis. Convergence insufficiency is a relatively common finding.
Systemic Findings
Hyperextensibility and fragility of the skin, and atrophic scars are characteristic. Joint hypermobility varies in degree among subtypes. In the vascular type, severe complications such as arterial dissection, aneurysms, and intestinal rupture occur.
A 46-year-old woman from Colombia took 40 years to be diagnosed with the myopathic type of EDS. She had dry eye and glaucoma, and systemically presented with easy fracturing, temporomandibular joint dislocation, and kyphoscoliosis 1).
QIs it possible to lose vision from EDS?
A
In brittle cornea syndrome (BCS), even minor trauma can cause corneal rupture, posing a risk of vision loss. In the kyphoscoliotic type, scleral fragility can lead to globe rupture. Additionally, retinal detachment associated with high myopia can cause vision loss. Early diagnosis and appropriate prevention of eye trauma are important.
EDS is caused by abnormalities in genes involved in collagen structure and modification. Mainly type I, III, and V collagens are involved. Type V collagen is the most abundant connective tissue protein in the cornea along with type I collagen, and haploinsufficiency of COL5A1 impairs the formation of heterotypic I/V fibrils 1).
The causative genes differ among subtypes. In the classical type, COL5A1/COL5A2; in the vascular type, COL3A1; in the kyphoscoliotic type, PLOD1 (lysine hydroxylase deficiency); and in BCS, ZNF469/PRDM5 have been identified 1). The classical-like type is due to deletion of TNXB (tenascin-X protein).
Having a first-degree relative with EDS is the greatest risk factor. Inheritance patterns include autosomal dominant (AD) and autosomal recessive (AR) depending on the subtype. Sporadic cases are due to de novo mutations.
Specific clinical diagnostic criteria are established for each subtype. In the classical type, skin hyperextensibility and atrophic scars with joint hypermobility are required. In BCS, corneal thinning (with keratoconus or keratoglobus) is a major criterion.
The Beighton score evaluates 5 types and 9 items: little finger dorsiflexion, thumb to forearm flexion, elbow and knee hyperextension, and trunk forward flexion. Age- and sex-specific cutoffs may be used.
Molecular diagnosis is recommended for all cases. DNA testing using next-generation sequencing (NGS) is utilized 1). In the kyphoscoliotic type, an elevated urinary deoxypyridinoline to pyridinoline ratio reflects decreased lysyl hydroxylase activity. In BCS, this ratio is normal.
Stickler syndrome (vitreoretinal abnormality, sensorineural hearing loss) and cutis laxa (sagging skin, normal wound healing) are also considered in the differential diagnosis.
There is no curative treatment for EDS. Treatment is primarily symptomatic, involving multidisciplinary management and genetic counseling1). All patients should undergo a complete ophthalmologic examination.
For retinal detachment, retinal reattachment surgery and vitrectomy are performed. In the ocular scoliosis type, surgical indications are determined under sufficient follow-up considering ocular fragility. There are also cases indicated for blepharoplasty or strabismus surgery. If corneal perforation occurs, tissue adhesive or structural corneal transplantation is required.
QIs ophthalmic surgery safe for EDS patients?
A
Surgery itself is possible, but it is known to have a higher complication rate than usual. Due to skin fragility, there is a risk of wound dehiscence and increased scarring, and it is desirable that EDS is diagnosed preoperatively. In some cases, surgery can be avoided by preventing trauma with protective eyewear, so please consult your ophthalmologist thoroughly.
Electron microscopy of EDS shows destruction of collagen fibrils, presenting a characteristic appearance called “collagen flowers.”
In the classical type, COL5A1/COL5A2 mutations cause abnormal type V collagen, and assembly of type I and III collagen is also impaired1). Although type V collagen is a minor component, it is widely distributed in tissues containing type I collagen (skin, tendons, ligaments, cornea, sclera). Dysregulation in heterotypic type I/V fibril formation is thought to underlie corneal thinning and eyelid laxity2).
In classic EDS (types I/II), mutations in COL5A1/COL5A2 cause impaired synthesis of type V collagen. Type V collagen is incorporated into type I collagen fibrils of the cornea and sclera. In EDS patients, laxity of the upper eyelids, reduced total type V collagen, and decreased corneal thickness have been reported 2). Abnormal interaction between type I and type V collagen has been hypothesized as a mechanism of floppy eyelid syndrome (FES) 3).
Keratoconus associated with EDS reflects increased degradation of corneal collagen. In keratoconus, elevated matrix metalloproteinase (MMP) activity and decreased tissue inhibitors of metalloproteinases (TIMPs) have been demonstrated 4). EDS, as a connective tissue disorder associated with abnormal collagen and hyperelasticity, is considered a risk factor for keratoconus4).
Vascular EDS (vEDS): COL3A1 mutations cause abnormal type III collagen, leading to fragility of arterial and intestinal walls. There is a risk of sudden death from arterial rupture in the 30s to 40s. Ocular complications may include internal carotid artery-cavernous sinus fistula and subretinal hemorrhage.
Kyphoscoliotic EDS (kEDS): Caused by lysyl hydroxylase deficiency due to PLOD1 mutations. Scleral fragility leads to globe rupture, lens dislocation, and retinal detachment.
The 2017 international classification established 13 subtypes 1), enabling precise subtype classification based on molecular diagnosis. With the widespread use of next-generation sequencing, the genetic basis of previously unclassified cases is being elucidated.
In fibroblasts from hypermobile EDS (hEDS), enhanced fibroblast-to-myofibroblast transition (FMT) has been demonstrated. This change, mediated by αVβ3 integrin-ILK-Snail1/Slug signaling, is noted as an abnormality in connective tissue remodeling.
Advances in corneal topography and tomography are enabling early detection of potential corneal ectasia in EDS patients 4). Regular corneal shape analysis in EDS patients is increasingly recommended.
The causative gene for hEDS has not yet been identified. Building evidence for chronic pain management is also an important challenge 1). In the ophthalmology field, clarification of the causal relationship between floppy eyelids and type V collagen abnormalities 2), development of corneal reinforcement methods for BCS, and improvement of safety in ophthalmic surgery for EDS patients are required.
Fajardo-Jiménez MJ, Tejada-Moreno JA, Mejía-García A, et al. Ehlers-Danlos: A Literature Review and Case Report in a Colombian Woman with Multiple Comorbidities. Genes. 2022;13(11):2118.
Salinas CM, et al. Floppy eyelid syndrome: A comprehensive review. Ocul Surf. 2020;18(1):1-9.
