Systematic ophthalmologic evaluation in cardio-facio-cutaneous syndrome: A genotype-endophenotype correlation.

Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder belonging to the RASopathies, a group of developmental syndromes caused by upregulated RAS/MAPK signaling. Pathogenic variants affecting four genes, KRAS, BRAF, MAP2K1 and MAP2K2, encoding core signal transducers of the pathway, underlie the condition. Major clinical features include a distinctive facies, ectodermal and cardiac anomalies, reduced postnatal growth, intellectual disability, and musculoskeletal abnormalities. Similar to other RASopathies, reports of visual impairment, high refractive error, optic nerve pallor, and other ocular abnormalities have been anecdotally reported in the literature. The aim of our study is to report the prevalence of ophthalmologic abnormalities in a large monocentric cohort of individuals affected by CFCS and explore the occurrence of genotype-endophenotype correlations in this series of patients. We observed that BRAF mutations are associated to a higher prevalence of anisometropia >3D (11.8% vs. 0%) and high astigmatism (29.4% vs. 0%; both p < 0.001) while patients with mutations in other genes had a significantly higher prevalence of myopia >6 D (60% vs. 5.9%; p = 0.012). Pale optic disc was associated with higher prevalence of inferior oblique muscle (IO) overaction (33.3% vs. 0%) and lower prevalence of ptosis (0% vs. 11.8%; both p < 0.001). Combined exotropia, IO overaction and nystagmus were frequent in patients with pale optic nerve. Our findings might suggest the need for earlier ophthalmologic referral for CFCS patients due to high risk of amblyopia, especially those expressing BRAF mutations.

Multimodal ocular imaging in Proteus syndrome.

In this report we illustrate the ophthalmologic assessment of two patients affected by Proteus Syndrome (PS), an extremely rare genetic disorder. Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. Case #2 describes a 20 year old female patient referred to our Ophthalmology Department for a routine ophthalmologic evaluation after being treated for 3 years with Miransertib (an experimental AKT-pathway inhibitor). Both patients underwent a complete ophthalmologic examination and a multimodal imaging evaluation. The multimodal imaging approach has revealed useful to evaluate both cases in detail and to keep track of disease evolution over time, moreover providing helpful features to further characterize this rare syndrome.

Long-term follow-up of surgical treatment of thyroid-associated orbitopathy restrictive strabismus.

Objective: Thyroid-associated orbitopathy (TAO) is the most frequent cause of extraocular muscle enlargement, with consecutive restrictive strabismus. The main muscles involved are inferior and medial rectus, resulting in horizontal esotropia and/or vertical strabismus. Surgery may either establish or improve binocular single vision. The aim of the present study is to describe long-term follow-up of patients who underwent horizontal or vertical TAO strabismus surgery. Methods: This observational retrospective study included 29 patients suffering from either vertical or horizontal TAO strabismus and diplopia, of whom 11 underwent bilateral medial recti muscle recession (Group A) and 18 underwent unilateral inferior rectus muscle recession (Group B). The endpoint of the study was the assessment of changes in deviation angle and diplopia across four time points (baseline, 7 days, 6 months, and 24 months) in each group. Results: In Group A, the horizontal deviation angle significantly decreased 7 days after intervention (p < 0.001), without modifications overtime. In Group B, both deviation angles in primary and down-gaze position significantly decreased from baseline, both 7 days after surgery (p < 0.001) and at 6 months (p = 0.040). An overcorrection, with an inversion of vertical deviation angle, was observed across the different time points. Conclusions: Horizontal TAO strabismus correction leads to significant improvements of deviation angle and diplopia, with a stable undercorrection overtime. Inferior rectus recession leads to more unstable results, with a trend towards overcorrection limited to the first 6 months after surgery.

OCT-Angiography Findings in Patients with Amblyopia: Comparison between Healthy Controls, Treatment-Responsive, and Treatment-Unresponsive Amblyopic Patients.

There is no consensus on whether amblyopia affects the retinal vascular plexus and morphology. Previous studies focused on the differences between amblyopic patients and normal controls without evaluating amblyopic eyes after patching. To evaluate differences in the superficial vascular density of amblyopic eyes, normal eyes, and amblyopic eyes reaching normal BCVA after patch therapy, OCTA was used. All patients underwent a comprehensive ophthalmological examination, including visual acuity, refraction, ocular motility tests, and anterior and posterior segment examination. OCTA was performed by an expert physician using the Zeiss Cirrus 5000-HD-OCT Angioplex (Carl Zeiss, Meditec, Inc., Dublin, OH, USA). OCTA scans were performed using a 3 × 3 mm2 and 6 × 6 mm2 fovea-centered image setting. The mean outer macular vessel density in the previously amblyopic group was 19.15 ± 0.51%. This was statistically significantly higher than in both the amblyopic group (18.70 ± 1.14%) and the normal controls (18.18 ± 1.40%) (p = 0.014). The previously amblyopic group also significantly differed from both normal controls and amblyopic eyes with regards to the inner (p = 0.011), outer (p = 0.006), and full (p = 0.003) macular perfusion. Finally, linear regression analysis revealed that BCVA was linearly correlated to outer perfusion in amblyopic (p = 0.003) and ex amblyopic eyes (p < 0.001). Considering the cross-sectional nature of our study, from our results, we can only hypothesize a possible correlation between light stimulation and retinal vasculature development. However, further longitudinal studies are needed to support this hypothesis.

Visual Function and Ophthalmological Findings in CHARGE Syndrome: Revision of Literature, Definition of a New Clinical Spectrum and Genotype Phenotype Correlation.

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype-ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype-phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do.

Embryopathy Following Maternal Biliopancreatic Diversion: Is Bariatric Surgery Really Safe?

Pregnancy after bariatric surgery is usually considered safe. Recently, a few studies reported that bariatric surgery represents a risk factor for birth defects. A case series of six patients, born from women who had undergone biliopancreatic diversion, is reported. The clinical pattern was characterized by psychomotor development delay (100%), microphthalmia (83%), growth retardation (66%), hearing loss (66%), and variable facial dysmorphism. Based on the clinical profile and symptoms reported by women during pregnancy, a causal association between maternal chronic post-surgical malabsorption, congenital anomalies, and neonatal outcome is proposed, with vitamin A deficiency representing a major causing factor. Educational follow-up support, continuous clinical monitoring, and appropriate nutritional assessment appear to be crucial to reduce the potential risk of congenital malformations and child disability.

Basedow-Graves' disease in a pediatric patient with Sticlker syndrome, a new endocrine finding to improve personalized treatment.

BACKGROUND: Stickler syndrome is a connective tissue disorder with predominantly autosomal dominant inheritance, with ocular, auditory and joint involvement. Thyroid dysfunction was not described as part of alterations in Stickler syndrome and in particular, the association between Stickler's syndrome and Graves' disease has never been previously reported in literature. Moreover, the presence of Graves' disease is uncommon in the pediatric age (especially in children younger than 6 years old). CASE PRESENTATION: We report the case of a 5-years old child affected by Stickler syndrome who received the diagnosis of Graves's disease, in absence of suggestive symptoms, during health supervision. CONCLUSIONS: This is the first evidence of thyroid dysfunction and autoimmune pattern for Sticker syndrome. Further clinical reports are expected before suggesting the implementation of new clinical skills for Stickler syndrome, but this paper may contribute to improve personalized management of this rare disorder.

The impact of strabismus surgery on gait pattern in patients with congenital or starting within one year of age strabismus.

Strabismus is a common visual disorder that negatively affects walking and balance. Therapeutic interventions for strabismus include strabismus surgery. Few studies investigated the relationship between strabismus surgery and postural control while, to the best of our knowledge, none has been conducted to assess the influence of strabismus surgery on gait. Therefore, the aim of this study was to evaluate the locomotion characteristics over patients with congenital or starting within one year of age strabismus, one month and three months after strabismus surgery. We enrolled 17 patients with a number of motor and sensorial features. Patients underwent an orthoptic and ophthalmological evaluation as well as a biomechanical evaluation before (T0) and after strabismus surgery (T1 at 1 month, and T2 at 3 months). We observed, mostly in T2 evaluation, significant improvements in the spatio-temporal parameters, such as cadence, velocity, swing, stance and double support phases, step and stride length. The kinematic results revealed a significant increase in hip ROM, strongly related to the improvement of gait speed. No significant differences has been observed in knee and ankle joint ROM. The kinetic results revealed a significant increase in the maximum moment at the knee and ankle joints associated with an increase in the maximum ankle power. Our findings suggest that the safety and balance control associated with gait improve in patients with strabismus following surgery.

Nerve growth factor improves visual loss in childhood optic gliomas: a randomized, double-blind, phase II clinical trial.

Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss. Presently there is no strategy to prevent visual loss in this kind of tumour. This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment. A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients, aged from 2 to 23 years, with stable disease and severe visual loss. Ten patients were randomly assigned to receive a single 10-day course of 0.5 mg murine nerve growth factor as eye drops, while eight patients received placebo. All patients were evaluated before and after treatment, testing visual acuity, visual field, visual-evoked potentials, optic coherence tomography, electroretinographic photopic negative response, and magnetic resonance imaging. Post-treatment evaluations were repeated at 15, 30, 90, and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days. Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days), which were not observed in placebo-treated patients. Furthermore, in patients in whom visual fields could still be measured, visual field worsening was only observed in placebo-treated cases, while three of four nerve growth factor-treated subjects showed significant visual field enlargement. This corresponded to improved visually guided behaviour, as reported by the patients and/or the caregivers. There was no evidence of side effects related to nerve growth factor treatment. Nerve growth factor eye drop administration appears a safe, easy and effective strategy for the treatment of visual loss associated with optic pathway gliomas.

The protean ocular involvement in monogenic autoinflammatory diseases: state of the art.

Ocular involvement is frequent in the monogenic autoinflammatory disorders and generally occurs as spontaneously recurring inflammatory events at different ocular sites caused by the aberrant release of proinflammatory cytokines, mainly IL-1ß. Over the past decade, we witnessed a significant growth of eye abnormalities associated with idiopathic granulomatous disorders, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and cryopyrin-associated periodic syndrome. The pathogenetic mechanisms of these disorders have shown the evidence of disrupted cytokine signaling, but the explanation for the heterogeneous ocular involvement remains to be elucidated. We herein review the monogenic autoinflammatory disorders affecting the eye, describing their main clinical features with specific regard to the ocular involvement, which can lead to decreased visual acuity and even blindness, if the primary disorder is undetected or left untreated.

Improved sensory status and quality-of-life measures in adult patients after strabismus surgery.

PURPOSE: To evaluate the change in sensory status and quality-of-life measures in adults with long-standing childhood-onset constant strabismus. METHODS: Consecutive patients with childhood-onset, long-term constant strabismus were enrolled. Sensory status was examined with Bagolini striated glasses test and Worth 4-dot test. Stereopsis was tested with the Lang and TNO stereopsis tests. Quality of life was studied with 2 different questionnaires (Short Form Health Survey [SF-36] and the Amblyopia and Strabismus Questionnaire [A&SQ]), which patients completed before and 3 months after strabismus surgery. RESULTS: A total of 20 patients (age range, 18-63 years) were included, 10 of whom were esotropic and 10 of whom were exotropic. Of these, 13 obtained a satisfactory postoperative alignment and demonstrated an increase of sensory status with Bagolini striated glasses. Six patients who demonstrated suppression preoperatively achieved fusion and stereopsis postoperatively. The mean score in all domains of the A&SQ improved significantly, particularly with regard to social contact and cosmesis (P = 0.00067), distance estimation (P = 0.000312), and visual disorientation (P = 0.004777). Similarly, the mean score in 7 of 8 areas in the SF-36 improved significantly, particularly with regard to physical function (P = 0.000564), general health (P = 0.002296), vitality (P = 0.002891), social function (P = 0.004234), and mental health (P = 0.000334). The overall mean score of both questionnaires improved in all patients with a satisfactory postoperative alignment and increase of sensory status. CONCLUSIONS: Surgical treatment of strabismus in adults with long-standing childhood-onset constant strabismus can result in patients feeling that their quality of life has improved and can restore binocular sensory function.

Prevalence of neurological involvement and malformative/systemic syndromes in A- and V-pattern strabismus.

PURPOSE: To evaluate the prevalence of neurological involvement and malformative/systemic syndromes in A- and V-patterns with respect to other kinds of infantile concomitant strabismus. METHODS: A retrospective comparative study of 14,006 consecutive patients examined in the Pediatric Ophthalmology and Strabismus Unit at the Catholic University of Rome between January 2002 and February 2010 was carried out. A total of 2.72% (385) of patients presented with concomitant constant infantile strabismus associated with A- and V- patterns (study group; mean age 8 years; range: 8 months - 37 years; male 211, female 174). Another 377 consecutive patients affected by infantile concomitant strabismus without A- or V- patterns were used as controls (control group; mean age 9 years, range: 1-34 years; male 194, female 183). All patients underwent a complete ophthalmologic and orthoptic examination with ocular motility evaluation and prism cover test or the Hirschberg test in primary, up and down gaze positions, as well as cycloplegic retinoscopy. The angle of deviation was evaluated at near (33 cm) and distance fixation (6 m) with full correction of refraction. RESULTS: Neurological involvement and malformative/systemic syndromes were observed in 30.4% of the study group and in 19.8% of patients in the control group (P < 0.001). Patients with A-pattern showed a greater prevalence of neurological impairment, hydrocephalus and meningomyelocele, while those affected by V-pattern exhibited a greater prevalence of craniosynostosis and malformative syndromes. CONCLUSIONS: Neurological involvement and malformative/systemic syndromes seem to be more evident in patients presenting with A- and V-pattern strabismus.

Measurement of retinal nerve fiber layer thickness, macular thickness, and foveal volume in amblyopic eyes using spectral-domain optical coherence tomography.

Although the changes in the anatomy of the visual cortex and lateral geniculate nucleus as the result of amblyopia have been well documented, retinal involvement is still controversial. Time-domain optical coherence tomography with an axial resolution of 10 µm has been used to evaluate retinal and peripapillary tissues in amblyopic eyes with contradictory results. Spectral domain optical coherence tomography has a greater resolution (5-10 µm) and can determine retinal layers more precisely. Our purpose was assess by means of spectral domain optical coherence tomography whether the retinal nerve fiber layer thickness, macular thickness, and foveal volume of the amblyopic and the fellow eyes differ in patients with unilateral amblyopia. Intereye differences in these parameters were found to be insignificant.

A morpho-functional study of amblyopic eyes with the use of optical coherence tomography and microperimetry.

PURPOSE: To determine whether retinal nerve fiber layer thickness (RNFLT), macular thickness, foveal volume, macular sensitivity, and fixation in patients with amblyopia differ between the amblyopic eye and the fellow eye. METHODS: Optical coherence tomography (OCT) and microperimetry (MP-1) were used to evaluate patients with unilateral amblyopia. Patients were divided into 2 groups, those with strabismic amblyopia and those with refractive amblyopia. OCT maps were used to calculate foveal volume, macular thickness, and RNFLT; MP-1 was used to determine macular sensitivity and fixation. RESULTS: A total of 30 patients were included (13 males; mean age 19.7 years [range, 10-38 years]), 15 in each group. Mean best-corrected visual acuity was 20/35 (range, 20/50 to 20/32) in the amblyopic eye and 20/21 (range, 20/20 to 20/25) in the fellow eye. In both groups, mean foveal volume and RNFLT did not differ significantly between eyes. Only macular thickness in the strabismic group differed significantly between the amblyopic and fellow eyes (P = 0.03). Macular sensitivity was significantly greater in the fellow eye in both groups (strabismic group, P = 0.002; refractive group, P = 0.013), whereas fixation did not change significantly between the amblyopic and fellow eye. RNFLT and macular sensitivity was found to be significantly correlated (strabismic group, r = 0.84, P = 0.002; refractive group, r = 0.66, P = 0.02). CONCLUSIONS: Our data suggest that although RNFLT does not vary between eyes, macular sensitivity is reduced in patients with amblyopia.

Effect of vertical transposition of the medial rectus muscle on primary position alignment in infantile esotropia with A- or V-pattern strabismus.

PURPOSE: To determine the effect of vertical displacement of muscle insertions on the surgical dose-response relationship in patients undergoing bilateral medial rectus recessions. METHODS: Retrospective chart review of patients undergoing bilateral medial rectus recessions for correction of congenital esotropia with or without vertical displacement for A or V patterns. Patients were clustered into A pattern, V pattern, and "simple" (no pattern) groups. Strabismus angle at distance and near before and after surgery was recorded. Surgical dose-response relationships (in prism diopters/mm) were determined at the 6-month follow-up visit and compared. RESULTS: A total of 55 patients (28 male and 27 female patients; mean age, 6.9 years; range, 2-17 years) were included. Of these, 28 had either A pattern (18) or V pattern (10), and 27 were in the simple group. Mean preoperative angle of deviation was 34Δ at distance and 40Δ at near. The surgical dose-response relationship was significantly greater (at both distance and near) in the A pattern group (2.43Δ/mm, distance [p=0.005]; 2.76Δ/mm, near [p=0.04]) than in the simple group (1.56Δ/mm, distance; 2.03Δ/mm, near). The surgical response in the V pattern group (1.96Δ/mm, distance [p=0.34]; 2.03Δ/mm, near [p=0.94]) was not significantly different from the simple group. CONCLUSIONS: Upward displacement of the medial rectus muscles increased the surgical dose/response relationship in patients with A-pattern esotropia. A similar effect was not observed with downward displacement in patients with V-pattern strabismus. Surgeons should be aware of this enhanced response when planning surgery for A-pattern esotropia.

Ocular manifestations in Wolf-Hirschhorn syndrome.

INTRODUCTION: Wolf-Hirschhorn syndrome (WHS) multiple congenital anomalies/mental retardation is caused by partial deletion of the short arm of chromosome 4 and can be considered a contiguous gene syndrome, characterized by typical facial appearance, mental retardation, growth delay, and seizures. METHODS: We investigated the ocular defects in a population of 10 patients with WHS and analyzed the relationship between ocular findings and the extent of deletion on chromosome 4. RESULTS: The ocular abnormalities found included hypertelorism, strabismus, refractive errors, epicanthal folds, proptosis, downslanting palpebral fissures, microphthalmos, microcornea, iris coloboma, optic nerve coloboma, ocular cyst, ptosis, glaucoma, and nystagmus. Different breakpoints of the chromosomal rearrangement were observed in individual patients, ranging from 4p15.1 to 4p16.3, and the size of chromosomal deletion ranged from 2.6 to 26 million base pairs. CONCLUSIONS: Congenital glaucoma and colobomatous ocular cysts have rarely been described in WHS patients that were previously reported. In all cases exhibiting strabismus, an exodeviation was present. Comparing genotype with ocular phenotype, a relationship between the size of deletion and the severity of the ocular involvement was observed in all cases but one.

Unilateral amblyopia: An optical coherence tomography study.

PURPOSE: To determine whether retinal nerve fiber layer thickness (RNFLT), macular thickness (MT), and foveal volume (FV) in patients with unilateral amblyopia differ between the amblyopic and the sound eye. METHODS: A Humphrey-Zeiss Stratus (OCT3) with software 4.0.3.1 was used to evaluate 40 patients (17 male, 23 female; mean age, 15.2 years; range, 5-56 years) with unilateral amblyopia. Patients were divided into 2 groups: 20 strabismic and 20 anisometropic. Maps of macular thickness and RNFL thickness (3.46) created by the use of optical coherence tomography were applied to calculate FV and MT and RNFLT. RESULTS: Mean best-corrected visual acuity was +0.3 LogMAR (range, +0.2 to +1.0) in the amblyopic eye. Mean RNFL thickness was not significantly different between eyes in either group. In strabismic amblyopia, mean MT and FV were 5% lower in the sound eye than in the amblyopic eye (MT, 267 microm vs 253 microm, p = 0.005; FV, 2.57 mm(3) vs 2.43 mm(3), p = 0.001). In anisometropic amblyopia, there was no significant difference between eyes in either MT or FV. CONCLUSIONS: In patients with strabismic amblyopia, the MT and FV were slightly but significantly lower in the sound eye than in the amblyopic eye. The clinical importance of this difference is not known. No such difference was observed in patients with anisometropic amblyopia.

Effect of oral CDP-choline on visual function in young amblyopic patients.

PURPOSE: The purpose of the study was to evaluate the effect on visual function of orally administered CDP-choline in addition to patching for the treatment of amblyopia in children. METHODS: This was an open label parallel group study comparing patching plus oral CDP-choline with patching alone. Sixty-one participants (aged between 5 and 10 years) suffering from anisometropic or strabismic amblyopia were divided at random into two groups: Group A, 800 or 1,200 mg (according to the body weight) of orally administered CDP-choline and 2-h patching a day; Group B, 2-h patching a day. Both groups were treated for 30 consecutive days. A follow-up visit was set 60 days after the treatment was discontinued. The main outcome measure was the change in visual acuity of amblyopic eyes as measured by Snellen's E charts. The secondary outcome measures were changes in the visual acuity of amblyopic eye as measured by isolated letters (Snellen's E) and changes in the contrast sensitivity of amblyopic eyes. RESULTS: The addition of CDP-choline to patching therapy was not found to be more effective than patching alone after 30-day treatment. The present results showed that adding CDP-choline to patching stabilised the effects obtained during the treatment period. In fact, whereas the participants treated only with patching showed a decrease in visual acuity at 90 days, these receiving CDP-choline and patching combined appeared to maintain the results obtained (two-way ANOVA: P = 0.0042). Similar results were obtained when measuring visual acuity by isolated Snellen's E letters. CONCLUSIONS: In amblyopic patients, CDP-choline combined with patching contributes to obtaining more stable effects than patching alone.