Ocular Features in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type: A Clinical and In Vivo Confocal Microscopy Study


To investigate ocular anomalies in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT).


Prospective, cross-sectional study.


Forty-four eyes of 22 consecutive patients with an established diagnosis of JHS/EDS-HT and 44 eyes of 22 age- and gender-matched control subjects. Administration of a standardized questionnaire (Ocular Surface Disease Index) and a complete ophthalmologic examination, including assessment of best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure measurement, indirect ophthalmoscopy, tear-film break-up time, Schirmer I testing, axial length and anterior chamber depth measurement, corneal topography, corneal pachymetry, and confocal microscopy. Main outcome measures included comparing ocular anomalies in JHS/EDS-HT and control eyes.


JHS/EDS-HT patients reported dry eye symptoms more commonly than controls ( P < .0001). Scores of tear-film break-up time and Schirmer I test were significantly lower in JHS/EDS-HT eyes ( P < .0001). Minor lens opacities were significantly more common in the JHS/EDS-HT group (13.6%; P < .05). Pathologic myopia with abnormal vitreous was found in 7 JHS/EDS-HT eyes (15.9%) and 0 controls ( P = .01). Corneas were significantly steeper and the best-fit sphere index was significantly higher in JHS/EDS-HT group ( P < .01). By confocal microscopy, the JHS/EDS-HT group showed lower density of cells in the superficial epithelium ( P < .001) and higher density of stromal keratocytes in anterior and posterior stroma ( P < .0001).


The most consistent association of eye anomalies in the JHS/EDS-HT group included xerophthalmia, steeper corneas, pathologic myopia, and vitreous abnormalities, as well as a higher rate of minor lens opacities. These findings indicate the need for ophthalmologic survey in the assessment and management of patients with JHS/EDS-HT.

Heritable connective tissue disorders refer to a wide range of genetic conditions caused by perturbed biogenesis of various components of the connective tissue. Ehlers-Danlos syndrome (EDS) comprises a clinically variable and genetically heterogeneous subgroup of heritable connective tissue disorders, mainly characterized by generalized joint hypermobility, skin hyperextensibility, and tissue fragility. Among the various EDSs, the hypermobility type (EDS-HT), now considered one and the same with joint hypermobility syndrome (JHS) by an international panel of experts, is likely the most common, with a presumed prevalence of 0.75% to 2% in the general population. JHS/EDS-HT is now considered the most debilitating form of EDS because of the high occurrence of disabling pain and fatigue. However, JHS/EDS-HT is difficult to recognize because of the absence of specific physical findings and known causative gene(s), except for a very few and still debated cases with mutations in tenascin XB and collagen type III α1 genes. Nevertheless, tenascin XB-deficient EDS recently was determined to be a distinct form of EDS by further phenotypic refinement. Accordingly, JHS/EDS-HT is still a diagnosis of exclusion based on internationally accepted clinical diagnostic criteria. However, the need for revising existing criteria is urgent.

Eye structures typically are involved in specific heritable connective tissue disorders, such as Stickler syndrome, which is characterized mainly by high myopia, vitreoretinal degeneration, and cataract. Among the various EDSs, diagnostic criteria for the kyphoscoliotic type comprise scleral fragility (major criteria) and microcornea (minor criteria). Ocular anomalies also have been included as a minor sign in the revised set of diagnostic criteria for JHS, but very few articles have been published on this topic. Mishra and associates first noted a high incidence of lid laxity and antimongoloid palpebral slants by evaluating 34 patients. Rarer features included myopia, congenital unilateral ptosis, and tilted optic disc. In a survey of Chilean patients, qualitatively assessed blue sclerae were considered common in JHS/EDS-HT. A single instrumental study by corneal topography was performed on 17 EDS-HT patients and failed to identify any specific change. The extreme variability of ocular involvement in heritable connective tissue disorders reflects the heterogeneity in composition of the fibrillar and nonfibrillar components of the connective tissue in the various structures of the eye.

This work is aimed at investigating ocular anomalies in 22 fully characterized JHS/EDS-HT patients compared with 22 age- and sex-matched controls. The findings may be relevant for interdisciplinary management issues of JHS/EDS-HT patients. They also may contribute toward understanding its complex, still largely unknown pathogenesis. Furthermore, some ocular features may be considered in future revisions of the JHS/EDS-HT diagnostic criteria.



Forty-four eyes of 22 patients (mean age ± standard deviation, 35.5 ± 12.1 years; range, 15 to 60 years; 18 women and 4 men) with an established diagnosis of JHS/EDS-HT and 44 eyes of 22 age- and sex-matched control subjects (mean age ± standard deviation, 35.6 ± 11.9 years; range, 14 to 60 years; 17 women and 5 men; P > .05 for age and sex) were included in this prospective, cross-sectional study. Patients were recruited consecutively at the joint hypermobility outpatient clinic of the Division of Physical Medicine and Rehabilitation of the Umberto I University Hospital, Rome, Italy, from October 2010 through March 2011. All patients were assessed originally in a multidisciplinary team including physiatrists (C.C., F.C.), physiotherapists, and a clinical geneticist (M.C.).

Diagnosis of JHS/EDS-HT was assessed applying published diagnostic criteria for JHS and EDS-HT. In clinical practice, the Brighton criteria are the most stringent for young adults, adults, and older patients, whereas the Villefranche criteria are the best for individuals in the pediatric age range. Patients were included if they met at least either 1 of these 2 sets of criteria. Both sets comprise generalized joint hypermobility as a major manifestation. Accordingly, generalized joint hypermobility was assessed following the Beighton score and was considered present with a score of at least 4 of 9 for the Brighton criteria and at least 5 of 9 for the Villefranche criteria ( Table 1 ). Further maneuvers also were applied to estimate joint mobility outside the joints evaluated for Beighton score calculation. Skin and superficial connective tissue aspects were assessed qualitatively on the basis of accumulated experience by palpation and gentle stretching of the skin at the volar aspect of the palm (at the IV metacarpal), forearm, or both. Healthy controls were enrolled consecutively among the unaffected companions of patients attending the outpatients department of the Eye Clinic of the Umberto I University Hospital from October 2010 through March 2011.


Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type: Applied Diagnostic Criteria

Brighton Criteria (Joint Hypermobility Syndrome) Villefranche Criteria (Ehlers-Danlos Syndrome, Hypermobility Type)
Major criteria Major criteria
Beighton score ≥ 4/9 Beighton score ≥ 5/9
Arthralgia for > 3 mos in > 4 joints Skin involvement (hyperextensibility, smooth, velvety skin, or both)
Minor criteria Minor criteria
Beighton score of 1-3 Recurring joint dislocations
Arthralgia in 1-3 joints Chronic joint/limb pain
History of joint dislocations Positive family history
Soft tissue lesions >3
Marfan-like habitus
Skin striae, hyperextensibility, or scarring
Eye signs, lid laxity
History of varicose veins, hernia, visceral prolapse

For the diagnosis, both major, or 1 major and 2 minor, or 4 minor criteria and the exclusion of other connective tissue disorders.

For both JHS/EDS-HT patients and controls, exclusion criteria were: positive history for lymphoproliferative disease, AIDS, sarcoidosis, diabetes mellitus, and corneal dystrophies or inflammations; ongoing systemic treatments with drugs with known corneal toxicity; use of antiglaucoma agents, anti-inflammatory agents, or both; and previous ophthalmic surgery.

Study procedures

All subjects underwent a complete ophthalmologic examination, including screening for strabismus using the corneal light reflection test and the cover test, assessment of Snellen best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure measurement with Goldmann tonometry, and indirect ophthalmoscopy.

Axial length and anterior chamber depth were measured using the Carl Zeiss IOLMaster, (version 4.07; Carl Zeiss Meditec, Dublin, California, USA). Tear film stability was evaluated by measuring the tear film break-up time (TBUT), after instillation of 1 μL of 0.5% unpreserved sodium fluorescein. Tear secretion was measured by the Schirmer I test under topical anesthesia (1 drop of 0.4% oxybuprocaine hydrochloride). All JHS/EDS-HT patients and control subjects were asked if they had any dry eye symptoms according to a standardized questionnaire (Ocular Surface Disease Index). Central corneal thickness was measured by ultrasonic pachymetry (A-Scan Pachymeter, model 5100e; DGH Technology, Inc, Exton, Pennsylvania, USA). The average of 3 measurements was taken as the central corneal thickness. Computerized corneal topography was performed using the Keratron Corneal Analyzer (software version 3.2; Optikon 2000, Rome, Italy). The 3-mm zone was examined using the simulated keratoscope reading and Maloney index analyses. Simulated keratoscope reading 1 (Sim K1) and simulated keratoscope reading 2 (Sim K2) represent the mean dioptric power along the steepest and the flattest meridian of the cornea, by definition 90 degrees apart. Simulated keratoscope difference represents the difference between Sim K1 and Sim K2. Maloney indices (best-fit sphere, best-fit cylinder, and topographic irregularity) were provided by the Keratron Corneal Analyzer. These indices are based on the spherocylinder, whose axial powers best fit the axial powers of the central 3-mm diameter of the corneal surface. By definition, the best-fit sphere index is the spherical power of the spherocylinder. The best-fit cylinder index is the difference in power between the principal meridians of the spherocylinder and measures regular corneal astigmatism. The topographic irregularity index is the error of the least squares fit of the spherocylinder. The refractive power (in diopters) at each point on the best-fit surface is determined. This is compared with measured power at the corresponding point on the topography map. The difference between these values is squared and added to a weighted running total for all points within the 3 mm of the corneal apex. Then, the square root of this sum is calculated as the topographic irregularity index.

In vivo confocal microscopy was performed by 1 masked expert (I.M.) operator, using the Confoscan 3.0 (Nidek Technologies, Vigonza, Italy). Examination was conducted in an area of approximately 440 × 330 μm at the corneal apex. A drop of anesthetic (oxybuprocaine chloride 0.4%) was instilled in the lower conjunctival fornix before examination. During the test, the objective lens of the microscope was covered by a gel hydroxypropilmetil cellulose 0.3%, Carbopol 980 (Noveon Europe, Brussels, Belgium), and never came in direct contact with the corneal surface. A drop of antibiotic (ofloxacin 0.3%) was instilled in the lower conjunctival fornix at the end of each examination, and the eye was re-examined at the slit lamp to verify the integrity of the corneal surface. A scan of the full thickness of the cornea was performed automatically for each participant; the examination lasted 1.5 to 2.5 minutes. Each scan recorded 350 images at a distance of 1.5 μm, on a z-axis, from one another. Each scan presented 2 to 4 complete passages from the endothelium to the superficial epithelium. Examinations were performed with a standard 40× objective lens. The z-scan curve (a graphic showing the depth coordinate on the z-axis and the level of reflectivity on the y-axis) of each scan was studied, and the images relative to the superficial and basal epithelium, to the anterior and posterior stroma, as well as to the subbasal plexus were selected. All areas of the z-scan curve, where the superficial epithelium and endothelium peaks were recognizable clearly, were considered. Cell densities of the superficial and basal epithelium and of the anterior and posterior stroma were evaluated. The first stroma photographic frame after an image of an endothelium and the last stroma photographic frame before an image referring to the basal epithelium were used to determine cell densities in the posterior and anterior stroma, respectively. In all cases, cell density was determined over a standardized area of 0.05 mm 2 , through the manual cell counting procedure present in the software. The cells partially contained in the area analyzed were counted only along the right and lower margins. Results were expressed in cells per square millimeter. The image of the subbasal plexus, where the highest number of nerve fibers was recognizable, was selected for each scan. Two parameters were taken into consideration: the number of nerves per frame (defined as the sum of the nerve branches observed in a frame) and tortuosity (evaluated and graded based on the scale proposed by Oliveira-Soto and Efron). Two independent, masked investigators (M.G., M.M.) analyzed the images, quantifying cell density in the different layers and number and tortuosity of the subbasal plexus nerve fibers. Patients and control subjects were tested with the same protocol.

Statistical analysis

Measurement values between groups were compared using Mann–Whitney rank-sum test. Categorical variables between the 2 study groups were compared using the Fisher exact test. Bivariate relationships were examined using the Spearman correlation coefficient. Correlation between ocular findings and Beighton score was not investigated because the latter cannot be considered a severity index for JHS/EDS-HT. Statistical significance was fixed at P ≤ .05. Interobserver variation was calculated by analyzing the variation coefficients of the different groups of data. Statistical analysis was performed with commercial software (SPSS for Windows, version 15.0; SPSS, Inc, Chicago, Illinois, USA).


Clinical findings

General characteristics of JHS/EDS-HT patients are shown in Table 2 . No patient was excluded based on the established criteria. Ocular findings are summarized in Table 3 . One JHS/EDS-HT patient (4.5%) showed bilateral prominent horizontal folds of upper lid skin and unilateral pseudoptosis versus 0 (0%) of 22 controls ( P > .05). TBUT and Schirmer I test scores in the JHS/EDS-HT group were significantly lower than those of controls ( P < .0001). Compared with control subjects, a significantly higher percentage of individuals in the JHS/EDS-HT group (0.39 ± 0.53 vs 2.32 ± 0.62; P < .0001) reported dry eye symptoms. Ocular refractive power, measured as spherical equivalent (diopters [D]) ± standard deviation), was not significantly different between groups (−2.14 ± 4.54 D; range, 2.25 to −21 D vs −0.51 ± 1.50 D; range, 4.5 to −3 D; P > .05).


Main Characteristics of Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type Group at the Beginning of the Study

Manifestation No. (Total, 22 Patients) %
Congenital joint hypermobility 15 68.2
Clumsiness in infancy 11 50.0
Beighton score ≥ 4 20 90.9
Chronic/recurrent (> 3 mos) arthralgias 21 95.4
Back pain 19 86.4
Chronic/recurrent myalgias 18 81.8
Recurrent sprains/strains 14 63.6
Recurrent dislocations 16 72.7
Recurrent (> 3) soft tissue lesions 11 50.0
Chronic fatigue 19 86.4
Soft, velvety skin 17 77.3
Hyperextensible skin 8 36.4
Easy bruising 16 72.7
Varicose veins 4 18.2
Abdominal hernias 1 4.5
Bladder/uterine/rectal prolapse 4 18.2
Limb paresthesias 16 72.7
Recurrent tachycardias 14 63.6
Gastrointestinal symptoms 17 77.3


Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type Group versus Controls: Clinical and Biometric Data

Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type (44 Eyes) Controls (44 Eyes) P Value
Contact lens use 10/44 6/44 .41 a
Questionnaire (mean ± SD) 2.32 ± 0.62 0.39 ± 0.53 <.0001 b
Snellen BCVA (mean ± SD) 0.98 ± 0.07 0.99 ± 0.03 .44 b
Spherical equivalent (D; mean ± SD) −2.14 ± 4.54 −0.51 ± 1.50 .42 b
Break-up time (sec; mean ± SD) 4.57 ± 1.73 11.53 ± 1.57 <.0001 b
Schirmer I test (mm/5 min; mean ± SD) 6.23 ± 2.50 13.39 ± 2.24 <.0001 b
Lens changes 6/44 0/44 .03 a
IOP (mm Hg; mean ± SD) 12.9 ± 1.58 13.5 ± 1.61 .26 b
ACD (mm; mean ± SD) 3.46 ± 0.33 3.47 ± 0.33 .79 b
AL (mm; mean ± SD) 24.4 ± 1.94 23.7 ± 1.24 .26 b
Pathologic myopia 7/44 0/44 .01 a

ACD = anterior chamber depth; AL = axial length; BCVA = best-corrected visual acuity; D = diopters; IOP = intraocular pressure; SD = standard deviation.

a Fisher exact test.

b Mann–Whitney rank-sum test.

Slit-lamp examination revealed lens opacities that did not affect visual acuity in 6 (13.6%) eyes in the JHS/EDS-HT group (patient mean age ± standard deviation, 29.4 ± 11.06 years; range, 15 to 39 years) versus 0 (0%) of 44 controls. One (4.5%) patient had bilateral discrete opacities in the fetal nucleus, and the remaining (18.2%) had minor unilateral subcapsular lens opacities ( Figure 1 ). One eye had myopia (−21 D; axial length, 32.37 mm), and the remaining were emmetropic (mean spherical equivalent ± SD, −0.10 ± 0.22 D; mean axial length, 23.2 ± 0.5 mm). The proportion of eyes with lens changes was significantly higher in the JHS/EDS-HT group ( P = .03).

Jan 12, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Ocular Features in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type: A Clinical and In Vivo Confocal Microscopy Study

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