OPA1 Dominant Optic Atrophy: Diagnostic Approach in the Pediatric Population.

A clinical and genetic study was conducted with pediatric patients and their relatives with optic atrophy 1 (OPA1) mutations to establish whether there is a genotype-phenotype correlation among the variants detected within and between families. Eleven children with a confirmed OPA1 mutation were identified during the study period. The main initial complaint was reduced visual acuity (VA), present in eight patients of the cohort. Eight of eleven patients had a positive family history of optic atrophy. The mean visual acuity at the start of the study was 0.40 and 0.44 LogMAR in the right and left eye, respectively. At the end of the study, the mean visual acuity was unchanged. Optical coherence tomography during the first visit showed a mean retinal nerve fiber layer thickness of 81.6 microns and 80.5 microns in the right and left eye, respectively; a mean ganglion cell layer of 52.5 and 52.4 microns, respectively, and a mean central macular thickness of 229.5 and 233.5 microns, respectively. The most common visual field defect was a centrocecal scotoma, and nine out of eleven patients showed bilateral temporal disc pallor at baseline. Sequencing of OPA1 showed seven different mutations in the eleven patients, one of which, NM_130837.3: c.1406_1407del (p.Thr469LysfsTer16), has not been previously reported. Early diagnosis of dominant optic atrophy is crucial, both for avoiding unnecessary consultations and/or treatments and for appropriate genetic counseling.

Whole Exome Sequencing of 20 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Cataracts.

Non-syndromic pediatric cataracts are defined as opacification of the crystalline lens that occurs during the first years of life without affecting other organs. Given that this disease is one of the most frequent causes of reversible blindness in childhood, the main objective of this study was to propose new responsible gene candidates that would allow a more targeted genetic approach and expand our genetic knowledge about the disease. We present a whole exome sequencing (WES) study of 20 Spanish families with non-syndromic pediatric cataracts and a previous negative result on an ophthalmology next-generation sequencing panel. After ophthalmological evaluation and collection of peripheral blood samples from these families, WES was performed. We were able to reach a genetic diagnosis in 10% of the families analyzed and found genes that could cause pediatric cataracts in 35% of the cohort. Of the variants found, 18.2% were classified as pathogenic, 9% as likely pathogenic, and 72.8% as variants of uncertain significance. However, we did not find conclusive results in 55% of the families studied, which suggests further studies are needed. The results of this WES study allow us to propose LONP1, ACACA, TRPM1, CLIC5, HSPE1, ODF1, PIKFYVE, and CHMP4A as potential candidates to further investigate for their role in pediatric cataracts, and AQP5 and locus 2q37 as causal genes.

Whole-Exome Sequencing of 21 Families: Candidate Genes for Early-Onset High Myopia.

High myopia is the most severe and pathological form of myopia. It occurs when the spherical refractive error exceeds -6.00 spherical diopters (SDs) or the axial length (AL) of the eye is greater than 26 mm. This article focuses on early-onset high myopia, an increasingly common condition that affects children under 10 years of age and can lead to other serious ocular pathologies. Through the genetic analysis of 21 families with early-onset high myopia, this study seeks to contribute to a better understanding of the role of genetics in this disease and to propose candidate genes. Whole-exome sequencing studies with a panel of genes known to be involved in the pathology were performed in families with inconclusive results: 3% of the variants found were classified as pathogenic, 6% were likely pathogenic and the remaining 91% were variants of uncertain significance. Most of the families in this study were found to have alterations in several of the proposed genes. This suggests a polygenic inheritance of the pathology due to the cumulative effect of the alterations. Further studies are needed to validate and confirm the role of these alterations in the development of early-onset high myopia and its polygenic inheritance.

Next-Generation Sequencing Screening of 43 Families with Non-Syndromic Early-Onset High Myopia: A Clinical and Genetic Study.

Early-onset high myopia (EoHM) is a disease that causes a spherical refraction error of ≥-6 diopters before 10 years of age, with potential multiple ocular complications. In this article, we report a clinical and genetic study of 43 families with EoHM recruited in our center. A complete ophthalmological evaluation was performed, and a sample of peripheral blood was obtained from proband and family members. DNA was analyzed using a customized next-generation sequencing panel that included 419 genes related to ophthalmological disorders with a suspected genetic cause, and genes related to EoHM pathogenesis. We detected pathogenic and likely pathogenic variants in 23.9% of the families and detected variants of unknown significance in 76.1%. Of these, 5.7% were found in genes related to non-syndromic EoHM, 48.6% in genes associated with inherited retinal dystrophies that can include a syndromic phenotype, and 45.7% in genes that are not directly related to EoHM or retinal dystrophy. We found no candidate genes in 23% of the patients, which suggests that further studies are needed. We propose a systematic genetic analysis for patients with EoHM because it helps with follow-up, prognosis and genetic counseling.

Automated Evaluation of Choroidal Thickness and Minimum Rim Width Thickness in Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: The aim of this study was to evaluate and compare peripapillary choroidal thickness (pCT) and macular choroidal thickness (CT), Bruch membrane opening-minimum rim width (BMO-MRW), retinal nerve fiber layer (RNFL) thickness, and optic disc area among nonarteritic anterior ischemic optic neuropathy (NAION) eyes, the contralateral unaffected eyes, and healthy control eyes. METHODS: Twenty-six patients diagnosed with NAION (29 affected and 21 unaffected eyes) and 29 healthy matched control individuals (29 eyes) were analyzed by swept-source optical coherence tomography. All participants underwent scanning by Spectralis optical coherence tomography to analyze BMO-MRW, RNFL thickness, and optic disc area. RESULTS: Mean pCT in the NAION eyes, unaffected fellow eyes, and the control group was 130.5 ± 72.1 µm, 149.6 ± 75.7 µm, and 103.7 ± 36.7 µm, respectively (analysis of variance [ANOVA], P = 0.04). Mean macular CT in the NAION eyes, unaffected fellow eyes, and the control group was 226.1 ± 79.8 µm, 244.6 ± 81.4 µm, and 189.9 ± 56.4 µm, respectively (ANOVA, P = 0.03). Mean and all sectorial RNFL and BMO-MRW thickness values were significantly thinner in the NAION eyes vs the unaffected fellow and control eyes (P ≤ 0.00). The unaffected fellow eyes in NAION patients showed a significantly thicker average and sectorial BMO-MRW values than control eyes (P ≤ 0.02) except for the nasal sector (P = 0.09). Mean optic disc area derived from BMO analysis was not significantly different among groups (ANOVA, P = 0.86). CONCLUSIONS: The fellow unaffected eyes in patients with NAION showed significantly thicker mean peripapillary and macular choroidal and BMO-MRW thicknesses than disease-free control eyes. No differences in the mean optic disc area were found. Both a thick peripapillary choroid and a thick neuroretinal rim might contribute to the development of NAION or possibly be a secondary phenomenon.

Recurrent ocular surface inflammation associated with human herpesvirus 6 infection.

OBJECTIVES: To report a case of atypical herpes keratitis and bilateral conjunctivitis associated with human herpesvirus 6 (HHV-6). METHODS: An immunocompetent 34-year-old man was referred for herpetic epithelial keratitis in his left eye, which was non-responsive to topical acyclovir. Biomicroscopy revealed a central dendritic ulcer with a white stromal infiltrate beneath the ulcer. RESULTS: The corneal scraping multiplex polymerase chain reaction (CLART ENTHERPEX, Genomica, Spain) was positive for HHV-6 and negative for herpes simplex virus, varicella zoster virus, cytomegalovirus, and Epstein-Barr virus. An improvement of the keratitis and visual acuity was achieved with topical fluorometholone and systemic valacyclovir. One year later, the patient complained of redness of the eyes. A slit-lamp examination disclosed bilateral follicular conjunctivitis, and HHV-6 DNA was once again detected in a conjunctival scraping of both eyes. CONCLUSIONS: Human herpesvirus 6 may be another causative agent for corneal ulcers and conjunctivitis in isolation. Stromal necrosis is a rare manifestation of herpetic dendritic keratitis. In these cases, we should consider the presence of HHV-6 in the differential diagnosis, even in immunocompetent patients.

Visual Outcomes, Visual Fields, and Optical Coherence Tomography in Paediatric Craniopharyngioma.

Ten patients with craniopharyngioma treated for the first time when younger than 18 were included. This study reviews the visual outcomes and provides information on visual field (VF) and optical coherence tomography (OCT) examination of craniopharyngioma. The best kappa concordance coefficients between VF and OCT parameters of atrophy were obtained for the ganglion cell (GC) thickness and the mean retinal nerve fibre layer (RNFL) thickness. The agreement between GC colour maps and VF defects was good. Optic nerve compression may be detected by RNFL measurement and GC analysis, and this may be valuable to predict visual recovery and in uncooperative patients to evaluate visual damage.

Visual field defects due to optic disk drusen in children.

BACKGROUND: Optic nerve head drusen (ONHD) are deposits due to abnormalities in axonal metabolism and degeneration. Studies so far have focused on adults. Our aim was to study the effect of ONHD on visual function as well as optic nerve head structure using optical coherence tomography (OCT) in children. METHODS: Subjects younger than 18 years of age with ONHD and who had a reliable visual field defect in at least one eye due to ONHD were considered for inclusion. All subjects underwent an extensive ophthalmic examination including best-corrected visual acuity (BCVA), funduscopy, and SITA 24-2 standard automated perimetry. OCT scanning was performed using Cirrus-HD Model 4000. Retinal nerve fiber layer (RNFL) thickness data were compared with a group of age-matched healthy children. RESULTS: Fifteen children were included, with a mean age of 13 years (range 7 to 17 years). BCVA was 1.0 in all eyes, except in a child with concomitant esotropia. ONHD were bilateral in 13 children. Among the 28 eyes with ONHD, 12 (43%) were classified as type 1 (buried), eight (29%) as type 2 (ringed) and eight (29%) as type 3 (superficial). All children had a visual field defect in at least one eye, according to the inclusion criteria; however, two eyes (7%) had no defect in spite of the presence of ONHD. Five eyes showed an isolated enlarged blind spot (18%), 15 cases showed a nasal defect (54%), and six eyes showed a constricted visual field (21%). RNFL thickness was higher in type 1 and 2 ONHD than in the control group, although these differences were only significant for the average, superior, and inferior quadrant thicknesses in type 1 and the inferior quadrant in type 2. RNFL thickness was lower in type 3 ONHD than in the control group, although these differences were only significant for the average, superior, and nasal quadrant thicknesses. CONCLUSIONS: ONHD may lead to the development of visual field defects, even in children. In initial stages, ONHD produce an increase in RNFL thickness as measured with OCT. As drusen develop and become superficial, the RNFL thickness decreases. The temporal quadrant is often undamaged, probably reflecting the preservation of central visual acuity.

Real-world evidence in achondroplasia: considerations for a standardized data set.

BACKGROUND: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes. METHODS: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes. RESULTS: A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments. CONCLUSIONS: Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.

Whole-Exome Sequencing of 24 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Keratoconus.

Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients. The presentation of this disease in pediatric age is associated with rapid progression, a worse prognosis and, in 15-20% of cases, the need for corneal transplantation. It is a multifactorial disease with genetic variability, which makes its genetic study difficult. Discovering new therapeutic targets is necessary to improve the quality of life of patients. In this manuscript, we present the results of whole-exome sequencing (WES) of 24 pediatric families diagnosed at the University Hospital La Paz (HULP) in Madrid. The results show an oligogenic inheritance of the disease. Genes involved in the structure, function, cell adhesion, development and repair pathways of the cornea are proposed as candidate genes for the disease. Further studies are needed to confirm the involvement of the candidate genes described in this article in the development of pediatric keratoconus.

Neovascular Glaucoma in Children: A case series and a review of the literature.

PURPOSE: To study the uncommon causes and treatment options for neovascular glaucoma in children. PATIENTS AND METHODS: A review of the literature on neovascular glaucoma in children was conducted and we present three cases of neovascular glaucoma in children. RESULTS: We present three cases of neovascular glaucoma: two cases were secondary to a retinal vasoproliferative tumor-one to neurofibromatosis type 1 and the other to exudative retinopathy secondary to mild retinopathy of prematurity-and one case was secondary to a central retina vein occlusion secondary to an optic nerve glioma. Vision in the affected eye was severely impaired in all the children. CONCLUSION: The diagnosis and treatment of neovascular glaucoma in children is challenging and often a complication of a systemic or late-stage ocular condition. An appropriate diagnosis and estimation of the visual potential are essential to determine the correct treatment, especially in young children.

Neuro-ophthalmological features of primary diffuse leptomeningeal gliomatosis.

We performed an in-depth study of the neuro-ophthalmologic signs and symptoms of a rare but fatal disease known as primary diffuse leptomeningeal gliomatosis (PDLG). Two new cases of PDLG are described, and 22 published cases reviewed. Papilledema and sixth nerve palsy are the most common neuro-ophthalmic findings. Other abnormalities include third and fourth nerve palsies, nystagmus, and vision loss. Involvement of the visual system may be part of the initial presentation of PDLG.

Primary Immunodeficiency Diseases Presenting with Chalazia as the First Manifestation.

Purpose: Ocular manifestations in primary immunodeficiency diseases are rare, but they can be the initial manifestation. This can lead to the prompt diagnosis and treatment of the disease and achieve a reduction of severe systemic complications.Case Report: We present two cases where a recurrent giant chalazion was the symptom that led to the diagnosis and early treatment of a patient with X-linked chronic granulomatous disease (CGD), and a patient with hyperimmunoglobulin E syndrome.Conclusion: Even though chalazia are common and benign, children presenting with recurrent giant chalazia or torpid evolution after surgery should be investigated for immunodeficiencies to reduce the severe and potentially fatal complications of the disease.

Expanding the Phenotypic Spectrum of PAX6 Mutations: From Congenital Cataracts to Nystagmus.

BACKGROUND: Congenital aniridia is a complex ocular disorder, usually associated with severe visual impairment, generally caused by mutations on the PAX6 gene. The clinical phenotype of PAX6 mutations is highly variable, making the genotype-phenotype correlations difficult to establish. METHODS: we describe the phenotype of eight patients from seven unrelated families with confirmed mutations in PAX6, and very different clinical manifestations. RESULTS: Only two patients had the classical aniridia phenotype while the other two presented with aniridia-related manifestations, such as aniridia-related keratopathy or partial aniridia. Congenital cataracts were the main manifestation in three of the patients in this series. All the patients had nystagmus and low visual acuity. CONCLUSIONS: The diagnosis of mild forms of aniridia is challenging, but these patients have a potentially blinding hereditary disease that might present with a more severe phenotype in future generations. Clinicians should be aware of the mild aniridia phenotype and request genetic testing to perform an accurate diagnosis.

Preseptal Versus Orbital Cellulitis in Children: An Observational Study.

BACKGROUND: Preseptal and orbital cellulitis are two types of infection surrounding the orbital septum with very different potential outcomes. Our aim was to describe key differential features of both conditions, laying special emphasis on diagnostic and therapeutic tools. METHODS: A retrospective review of patients admitted to a tertiary hospital over a 15-year period (January 2004-October 2019) was conducted. We included 198 patients with preseptal and 45 with orbital cellulitis. Descriptive statistics were performed to examine the available information. RESULTS: Statistically significant differences were found between patients with preseptal and orbital cellulitis regarding age (3.9 ± 2.14 vs. 7.5 ± 4.24 years), presence of fever (51.5% vs. 82.2%), and preexisting sinusitis (2% vs. 77.8%) (all P < 0.001). Diplopia, ophthalmoplegia and proptosis were only present in orbital cellulitis (P < 0.001). Median values of C-reactive protein were significantly higher among children with orbital involvement [136.35 mg/L (IQR 74.08-168.98) vs. 17.85 (IQR 6.33-50.10), P < 0.0001]. A CRP>120 mg/L cut-off point for orbital cellulitis was obtained. Early CT scans were performed in 75.6% of suspected orbital cellulitis and helped detecting complications at an early stage. Abscesses were revealed in 70.6% of cases, especially medial subperiosteal abscesses (58.8%). All patients received intravenous antibiotics, whereas corticosteroids were preferred in patients with orbital implication (8.6% vs. 73.3%, P < 0.001). Only 26.7% of patients required additional surgery. CONCLUSIONS: Clinical presentation and CRP are extremely sensitive for differential diagnosis of preseptal and orbital cellulitis. Prompt initiation of intravenous antibiotics is mandatory and can prevent surgical procedures even in cases with incipient abscesses.

Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families.

Our purpose was to identify mutations responsible for non-syndromic congenital cataracts through the implementation of next-generation sequencing (NGS) in our center. A sample of peripheral blood was obtained from probands and willing family members and genomic DNA was extracted from leukocytes. DNA was analyzed implementing a panel (OFTv2.1) including 39 known congenital cataracts disease genes. 62 probands from 51 families were recruited. Pathogenic or likely pathogenic variants were identified in 32 patients and 25 families; in 16 families (64%) these were de novo mutations. The mutation detection rate was 49%. Almost all reported mutations were autosomal dominant. Mutations in crystallin genes were found in 30% of the probands. Mutations in membrane proteins were detected in seven families (two in GJA3 and five in GJA8). Mutations in LIM2 and MIP were each found in three families. Other mutations detected affected EPHA2, PAX6, HSF4 and PITX3. Variants classified as of unknown significance were found in 5 families (9.8%), affecting CRYBB3, LIM2, EPHA2, ABCB6 and TDRD7. Mutations lead to different cataract phenotypes within the same family.

Ophthalmic features of spinocerebellar ataxia type 7.

BACKGROUND: Patients with spinocerebellar ataxia 7 (SCA7) are known to develop ocular abnormalities. The purpose of this study was to characterize these abnormalities in greater detail and with the aid of newer quantitative technologies. METHODS: Seven patients with SCA7 diagnosed by genetic analysis at La Paz Hospital (Madrid, Spain), a country-wide referral center for ataxias, were included in the study. Demographic data and ocular features were recorded from a complete ophthalmologic examination, specular microscopy, corneal topography (Pentacam), and optical coherence tomography (OCT). RESULTS: All 7 patients had decreased visual acuity associated with varying degrees of macular pigmentary changes on ophthalmoscopy. All 7 had lower corneal endothelial cell densities than expected for their age, and 5 had increased corneal volume, although none had corneal edema. Patients with mild disease showed retinal thinning at the fovea. In patients with more advanced disease, retinal thinning was present also in the outer zone of the macula. Mean peripapillary retinal nerve fiber layer thickness was decreased in all patients; however, the temporal quadrant was spared except in advanced disease. CONCLUSIONS: This study of 7 patients with SCA7 amplifies previous reports of ophthalmic abnormalities in this condition by providing data from specular microscopy, corneal topography, and OCT. Abnormalities were present in the anterior and posterior ocular segments, as well as in eye movements and pupillary reactions. Visual dysfunction, present in all patients, was associated with retinal thinning. Decreased endothelial cell density and increased corneal thickness were common.

HGF-rs12536657 and Ocular Biometric Parameters in Hyperopic Children, Emmetropic Adolescents, and Young Adults: A Multicenter Quantitative Trait Study.

INTRODUCTION: Even though ocular refractive state is highly heritable and under strong genetic control, the identification of susceptibility genes remains a challenge. Several HGF (hepatocyte growth factor) gene variants have been associated with ocular refractive errors and corneal pathology. PURPOSE: Here, we assess the association of an HGF gene variant, previously reported as associated with hyperopia, and ocular biometric parameters in a multicenter Spanish cohort. METHODS: An observational prospective multicenter cross-sectional study was designed, including a total of 403 unrelated subjects comprising 188 hyperopic children (5 to 17 years) and 2 control groups: 52 emmetropic adolescents (13 to 17 years) and 163 emmetropic young adults (18 to 28 years). Each individual underwent a comprehensive eye examination including cycloplegic refraction, and topographic and ocular biometric analysis. Genomic DNA was extracted from oral swabs. HGF single nucleotide polymorphism (SNP) rs12536657 was genotyped. Genotypic, allelic, and logistic regression analyses were performed comparing the different groups. A quantitative trait association test analyzing several biometric parameters was also performed using generalized estimating equations (GEEs) adjusting for age and gender. RESULTS: No association between rs12536657 and hyperopia was found through gender-adjusted logistic regression comparing the hyperopic children with either of the two control groups. Significant associations between mean topographic corneal curvature and rs12536657 for G/A (slope = +0.32; CI 95%: 0.04-0.60; p=0.023) and A/A (slope = +0.76; CI 95%: 0.12-1.40; p=0.020) genotypes were observed with the age- and gender-adjusted univariate GEE model. Both flat and steep corneal topographic meridians were also significantly associated with rs12536657 for the G/A and A/A genotypes. No association was found between rs12536657 and any other topographic or biometric measurements. CONCLUSIONS: Our results support a possible role for HGF gene variant rs12536657 in corneal curvature in our population. To our knowledge, this is the first multicenter quantitative trait association study of HGF genotypes and ocular biometric parameters comprising a pediatric cohort.

Optic disc evaluation by optical coherence tomography in nonarteritic anterior ischemic optic neuropathy.

PURPOSE: To describe the characteristics of the optic nerve head (ONH) in patients with nonarteritic anterior ischemic optic neuropathy (NAION) and compare them with control subjects by using optical coherence tomography (OCT). METHODS: Patients with NAION underwent a complete ophthalmic examination, including OCT scanning of the ONH at diagnosis. The examination was repeated 1.5, 3, and 6 months later. Age- and sex-matched control subjects with no ocular disease underwent a similar evaluation. Data were obtained by using the ONH analysis protocol of the StratusOCT (Carl Zeiss Meditec, Dublin, CA). RESULTS: Twenty-three patients and 23 control subjects were included. In eyes with NAION, the vertical integrated rim area decreased significantly (P < 0.01) from the acute phase to the 6-month visit. The cup-to-disc (C/D) area ratio increased significantly (P = 0.002) from the acute examination to the 3-month visit. There was a significant difference between the NAION fellow eyes and the control eyes in C/D ratio, evaluated by slit lamp funduscopy (P < 0.001), and in the C/D area ratio (P = 0.001). The vertical integrated rim area was significantly (P = 0.001) greater in NAION fellow eyes than in control eyes. There was no significant difference in optic disc area or vertical disc diameter among the control eyes, NAION-affected eyes, and NAION fellow eyes. CONCLUSIONS: Although patients with NAION have lower C/D ratios than does the normal population, with a higher level of nerve fiber crowding, there was no difference in optic disc size between patients with NAION and control subjects. After the development of NAION, 47.8% of eyes had a C/D ratio that differed from that in the fellow eye by more than 0.1.