Ocular Findings in Benign Joint Hypermobility Syndrome Patients

Objectives: To evaluate the prevalence and characteristics of ocular findings in a sample of Iraqi patients with (BJHS). Patients and Methods: This cross-sectional study included 100 patients diagnosed with BJHS according to Brieton criteria and another 200 healthy controls matched in age and sex. Demographics were collected, and full ophthalmological examination was done on both groups. Results: Prevalence of refractive errors was 78% of them: myopia was 49%, followed by astigmatism 20%) and hypermetropia 9%. The other identified ocular manifestation was dry eye (15%), while anterior & posterior blepharitis 5% and 4% respectively. Pigment dispersion syndrome was diagnosed in 3% of patients and the cataract was 2% of BJHS patients. All previous findings were statistically significant except cataract not reach to statistically significant level. Conclusions: Ocular findings in BJHS were relatively common. The most common BJHS-related ocular findings were myopia followed by astigmatism and hypermetropia. Dry eye symptoms, anterior and posterior blepharitis, pigment dispersion syndrome and cataract are rare in patients with BJHS.


Introduction
Benign Joint Hypermobility Syndrome (BJHS) is an inherited connective tissue disease, distinguished by musculoskeletal pain and an excessive range of motion in joints 1 . With the absence of systemic rheumatological disease 2 . Many ocular manifestations of BJHS have been described, some being well-known associations and others reported for the first time in case report 3 . In a survey of Chilean patients, qualitatively assessed blue sclerae were considered common on Benign Joint Hypermobility Syndrome/Ethlers Danols Syndrome Hypermobility Type (BJHS/EDSHT) 4 . Few ocular complications of EDS, including eyelid and conjunctiva abnormalities, keratoglobus corneal thinning and keratoconus, dry eye, pathologic myopia, angioid streaks and abnormal retinal vessels, retinal detachment, scleral atrophy, and globe perforation [5][6][7][8] .
Because of limited reports on prevalence of ocular manifestations, this study was designed to assess ocular manifestations in a sample of Iraqi patients with benign joint hypermobility

Study Design
This cross-sectional study was conducted at the Rheumatology Unit, Department of Medicine in Baghdad Teaching Hospital from August 2015 to April 2016.

Sample Selection
A total of 300 subjects were enrolled in the study, 100 of them were diagnosed as benign hypermobility syndrome and 200 were controls. JHMS is diagnosed according to the Brighton criteria 2 .
Informed consent was obtained from each participant included in this study according to the declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of Baghdad University, College of Medicine, and Medical Department.
Patients were excluded from the study if they had history of previous eye trauma, hypertension, diabetes mellitus, and overlap with other connective tissue diseases or inflammatory arthritis.

Data Collection and Measurements
Interview questionnaire included ages, gender, and joint pain. Occular manifestations in all subject-IOS were evaluated by an ophthalmologist blinded to the diagnosis. at Ophthalmology Unit in Ghazi-Alharery Teaching Hospital. Ophthalmological examination included visual acuity assessment with Snellen charts, examination of anterior and posterior eye segments with the slit lamp, Schirmer test and corneal fluorescein staining, and assessment of intraocular pressure with Goldman applanation tonometer. Indirect ophthalmoscopy was performed with an indirect ophthalmoscope and a 20-diopter lens after both pupils were dilated with 1% tropicamide for some patients need diltation, the posterior pole was further evaluated by slitlamp bio microscopy using a 78-D Volk lens.

Statistical Analysis
Statistical analyses were done using SPSS version 21. Normal distribution for continuous variables was done first. Independent samples t-test was used to measure the difference between means of 2 groups of normally distributed variables. Chi-square test was used to assess the statistical significant difference between 2 categorical variables or Fisher's exact was used when Chi-square test was inappropriate.
The 95% CI: the 95% confidence interval is a statistical procedure to anticipate or predict the expected range of possible values of the calculated sample estimate of any statistic in the reference population with 95% confidence. To measure the strength of association between 2 categorical variables, such as the presence of certain risk factor and disease status the Odds Ratio (OR) was measured using binary logistic regression analysis. Differences with P value <0.05 were considered statistically significant.

Results
Three hundred subjects were involved in this study, BJHS were 100 and healthy controls were 200. The mean age, gender, and body mass index of patients were not statistically significantly different from that of controls (p>0.05) as in Table 1.
( Table 2) myopia, stigmatism, dry eye, anterior blepharitis, posterior blepharitis, and pigment dispersion syndrome, were significantly more frequent among patients with hypermobility syndrome than the control group (P<0.05). Cataract and hypermetropia were slightly more frequent in patients group, but the differences observed were too small to be of statistical significance (p>0.05).
The risk of having Dry eye is increased by 72.7 times in cases with hypermobility syndrome, while that of anterior blepharitis is increased by 23.1 times and that of posterior blepharitis is increased by 18.7 times compared to controls. In addition, the risk of having pigment dispersion syndrome, myopia and Astigmatism is significantly increased by 14.4, 11.1 and 3.9 times respectively among cases with hypermobility ( Table 2).

Discussion
Few reports are present on ocular complications in BJHS. Up to our knowledge, this is the first study t that evaluated the prevalence and characteristics of ocular manifestations in Iraqi patients with BJHS. Interestingly, refractive was the most frequent finding and detected in 78% patients, while myopia was detected in (49%), followed by astigmatism (20%) and hypermetropia (9%) & these results were statistically significant in this study.
Refractive errors may be explained by that, alterations in any sclera, vitreous extracellular matrix components, or both are likely to change scleral shape, vitreous structure, or both, which in turn could affect the axial length of the eye 11 , another explation suggested that alterations of the fibrillar components of the connective tissue (collagen types I, III, and V) are involved in EDS variants that are clinically distinct from BJHS 9 .
The molecular defect underlying BJHS may reside in genes encoding non-fibrillar components of the extracellular matrix or enzymes involved in their posttranslational maturation. In particular, mutations in various small leucin rich proteoglycans were associated with both EDS-like phenotypes and myopia in mice [9][10] . Therefore, they all may be possible candidates for BJHS in humans. In Wegener et al study 12 prevalence of myopia combined with astigmatism was 33% and that of hyperopia combined with astigmatism 28%, this was statistically significant.
On other hand in study 13 , conventional ophthalmologic and special somatic examination was carried out on patients with myopia and control group showed that, all the patients with high myopia showed 12 various additional features of connective tissue hyperelasticity, on the average, with no more than 4 such features in the control group.
The other identified ocular manifestation in this study was dry eye symptoms (15%). and this finding is in agreement with previous observation 3 .
The cause of xerophthalmia in BJHS is unknown, but some research ESR suggest that tear production is strongly influenced by the autonomic nervous system, a possible autonomic dysfunction underlying tear production deficiency may be put forward. This hypothesis is in line with the repeated observation of cardiovascular dysautonomia signs and symptoms, including palpitations, arrhythmias, postural orthostatic tachycardia, and syncope 14 .
Tear secretion impairment may be result from developmental alterations of the lacrimal gland extracellular matrix, because it may play a role in regulating lacrimal gland secretion, this abnormal extracellular matrix production may be linked to an inherited defect of a non-fibrillar component of the connective tissue 15 .
The other identified ocular manifestation in this study was anterior & posterior blepharitis (5% and 4%) respectively and these results are statistically significant. blepharitis is a common, chronic, and potentially sight-threatening eyelid and ocular surface disease, characterised by inflammation and obstruction of the meibomian glands [16][17] . To the best of our knowledge no other study reported these findings in BJHS, the cause of this finding in BJHS may be related to different genetic and environmental factors. Another observed ocular finding in this study was pigment dispersion syndrome which presented in (3%) of patients Dwith BJHS, and this finding reached a statistically significant level. Pigment dispersion Syndrome (PDS) is an ocular condition characterized by a dispersion of iris pigment throughout the eye due to idiopathic atrophy of the pigment layers of the iris 18 . The molecular mechanism causing PDS and the pathway by which it progresses to pigmentary glaucoma is not known. Up to our knowledge no other study reported that finding, and its presence in patients with BJHS can be explained by various genetic and environmental factors.
Finally, in this study was cataract was present (2%) of BJHS patients, but this finding did not reach a statistically significant level, and it is in disagreement with another study 6 which showed that minor lens opacities present in a statistically significant number of patients and this disagreement between the two studies may be due to sample size and differences in genetic and environmental factors between the two populations.
The current study is limited by small sample size that can be solved by a larger and longer prospective study to validate our findings. Furthermore, we reported a selected group of patients referred to tertiary care, so our findings cannot be generalized to patients in primary care so selection bias might be present. Nevertheless; it is accepted that the investigators may have introduced selection bias in those patients with more severe symptoms. In spite of these limitations, the current study revealed a significant clinical application of the association between BJHS & ocular findings that ignited a considerable clinical interest which may help physicians to early recognition of these findings and subsequently to ensure correct diagnosis and treatment , although small number of studies were similar to the current study but the discordant results suggests the need to conduct more studies with a larger population in different parts of the world with various races.

Conclusions
In ocular findings of BJHS were relatively common. Refractive errors symptoms were the most common BJHS related ocular findings followed by myopia, astigmatism and hypermetropia. Dry eye symptoms, anterior and posterior blepharitis, pigment dispersion syndrome and cataract were rare in patients with BJHS. These results suggest that Early and frequent eye monitoring for patients with BJHS to early diagnose and treat the ocular findings and to recognize patients with milder phenotypes on the basis of minor ocular changes (e.g., increased corneal refractive power and lens opacities). Therefore, ophthalmologic consultation should be scheduled not only in BJHS patients, but all individuals with suspected heritable connective tissue disorder to define the diagnosis better.