Search

OBJECTIVE: To assess the prevalence, risk factors, and long-term outcome of uveitis in patients with juvenile idiopathic arthritis (JIA). METHODS: An inception cohort of all 1,081 patients diagnosed as having JIA at a single tertiary care center was established. A questionnaire and followup telephone calls were used to confirm the diagnosis of uveitis. Ophthalmologists' records of patients with uveitis were collected. Kaplan-Meier and Cox regression analyses were used to assess risk factors for developing uveitis and for complications of uveitis. RESULTS: After a mean followup time of 6.9 years, 142 of 1,081 patients (13.1%) had developed uveitis. Risk factors were young age at diagnosis, female sex, antinuclear antibody positivity, and the subtype of JIA. The relative contribution of these risk factors was different for the different subtypes of JIA. Until the end of the study, uveitis complications had developed in 53 of 142 patients with uveitis (37.3%; 4.9% of the total cohort). Only 16 of 175 involved eyes (9.1%) in 14 of 108 patients (13%; 1.3% of the total cohort) for whom ophthalmology reports were available had best corrected visual acuity less than 20/40 (mean followup time for uveitis of 6.3 years). Abnormal vision was associated with synechiae or cataract. CONCLUSION: Risk factors for developing uveitis were different among subtypes of JIA. The long-term outcome of JIA-associated uveitis in our cohort was excellent despite the high rate of complications. [ABSTRACT FROM AUTHOR]

Abstract A correlation between increase in the integration of Human Immunodeficiency virus-1 (HIV-1) cDNA and cell death was previously established. Here we show that combination of peptides that stimulate integration together with the protease inhibitor Ro 31-8959 caused apoptotic cell death of HIV infected cells with total extermination of the virus. This combination did not have any effect on non-infected cells. Thus it appears that cell death is promoted only in the infected cells. It is our view that the results described in this work suggest a novel approach to specifically promote death of HIV-1 infected cells and thus may eventually be developed into a new and general anti-viral therapy.

Abstract Background The presence of the cellular Lens Epithelium Derived Growth Factor p75 (LEDGF/p75) protein is essential for integration of the Human immunodeficiency virus type 1 (HIV-1) cDNA and for efficient virus production. In the absence of LEDGF/p75 very little integration and virus production can be detected, as was demonstrated using LEDGF/p75-knokdown cells. Results Here we show that the failure to infect LEDGF/p75-knockdown cells has another reason aside from the lack of LEDGF/p75. It is also due to inhibition of the viral integrase (IN) enzymatic activity by an early expressed viral Rev protein. The formation of an inhibitory Rev-IN complex in virus-infected cells can be disrupted by the addition of three IN-derived, cell-permeable peptides, designated INr (IN derived-Rev interacting peptides) and INS (IN derived-integrase stimulatory peptide). The results of the present work confirm previous results showing that HIV-1 fails to infect LEDGF/p75-knockdown cells. However, in the presence of INrs and INS peptides, relatively high levels of viral cDNA integration as well as productive virus infection were obtained following infection by a wild type (WT) HIV-1 of LEDGF/p75-knockdown cells. Conclusions It appears that the lack of integration observed in HIV-1 infected LEDGF/p75-knockdown cells is due mainly to the inhibitory effect of Rev following the formation of a Rev-IN complex. Disruption of this inhibitory complex leads to productive infection in those cells.

Abstract Background The integrase (IN) of human immunodeficiency virus type 1 (HIV-1) has been implicated in different steps during viral replication, including nuclear import of the viral pre-integration complex. The exact mechanisms underlying the nuclear import of IN and especially the question of whether it bears a functional nuclear localization signal (NLS) remain controversial. Results Here, we studied the nuclear import pathway of IN by using multiple in vivo and in vitro systems. Nuclear import was not observed in an importin α temperature-sensitive yeast mutant, indicating an importin α-mediated process. Direct interaction between the full-length IN and importin α was demonstrated in vivo using bimolecular fluorescence complementation assay (BiFC). Nuclear import studies in yeast cells, with permeabilized mammalian cells, or microinjected cultured mammalian cells strongly suggest that the IN bears a NLS domain located between residues 161 and 173. A peptide bearing this sequence -NLS-IN peptide- inhibited nuclear accumulation of IN in transfected cell-cycle arrested cells. Integration of viral cDNA as well as HIV-1 replication in viral cell-cycle arrested infected cells were blocked by the NLS-IN peptide. Conclusion Our present findings support the view that nuclear import of IN occurs via the importin α pathway and is promoted by a specific NLS domain. This import could be blocked by NLS-IN peptide, resulting in inhibition of viral infection, confirming the view that nuclear import of the viral pre-integration complex is mediated by viral IN.

Four infants developed invasive Pseudomonas aeruginosa ophthalmic infections between 5 and 90 days of age. Three died from septicaemia, and the fourth required enucleation of one eye. Absent red reflexes or other eye signs in a septicaemic infant merit urgent ophthalmological assessment for endophthalmitis, in particular, Pseudomonas. [ABSTRACT FROM AUTHOR]

Importance: Alström syndrome is a rare genetic disorder characterized by retinopathy and has life-threatening complications. Alström syndrome is frequently misdiagnosed or confused with other early childhood disorders with retinopathy.  Understanding the spectrum of ocular manifestations of Alström syndrome is essential for ophthalmologists to recognize the cause and institute-appropriate care for this disorder that requires multidisciplinary attention., Objective: To quantify and summarize the common ocular findings of Alström syndrome., Design: Case series, clinical exam data obtained from 2015 to 2023., Setting: Semiannual multidisciplinary Alström syndrome clinics (2015-2023) at the Greater Baltimore Medical Center (GBMC), organized by Alström Syndrome International (ASI)., Participants: Forty-eight patients (38 children, 10 adults) with a known diagnosis of Alström syndrome participated in the semiannual multidisciplinary Alström syndrome clinics. Patients apply to be seen and are accepted based on need and capacity., Intervention(s) or Exposure(s): Not applicable., Main Outcome(s) and Measure(s): Clinical ocular findings., Results: Participants in this study had a median age of 8 years (15 months to 42 years). Visual acuity and progression of vision loss varied. The youngest patient who was legally blind was 2 years old. The oldest patient who maintained useful vision was 7 years old. All patients 8 years old or older were legally blind. Nystagmus (94%, 45 of 48) and photophobia (73%, 35 of 48) were the most common first presenting ocular symptoms in childhood. Retinal vascular attenuation (91%, 40 of 44) and retinal internal limiting membrane changes (68%, 30 of 44) were the most commonly documented retinal findings in both children and adults followed by optic nerve (ON) pallor and retinal pigment epithelium (RPE) mottling. Less than half of the children had ON pallor (38%, 14 of 37) and RPEmottling (38%, 14 of 37), while all adults had these two findings (100%, 7 of 7). Retinal pigment clumps were not common in children (11%, 4 of 37), while common in adults (86%, 6 of 7)., Conclusions and Relevance: Knowledge of these ocular findings is key to promptly recognize Alström syndrome. The ocular phenotype of Alström syndrome is largely dependent on age, suggesting that low vision interventions and potential gene-based therapeutics should target children with this disorder.

Purpose: To evaluate the clinical presentation, course, and outcomes of uveitis in paediatric patients with tubulointerstitial nephritis and uveitis syndrome (TINU)., Methods: Multicentric Retrospective Cohort Study 110 patients ≤21 years of age diagnosed with TINU from 10 sites across the United States and Canada. Clinical diagnosis of TINU required uveitis diagnosed by an ophthalmologist, elevated serum creatinine (SCr) and elevated urine β2-microglobulin (β2M) or abnormal urinalysis. Renal biopsy and systemic illness were not mandatory. Univariate and multivariate analysis was performed to analyse risk factors and treatment modalities., Results: Median age was 13 years (Range (5.9-18.4); 52% male); median follow-up, 1.6 years (IQR 0.98-4.02). Uveitis was symptomatic in 90%, with bilateral anterior uveitis in 94%. Ninety-two (84%) patients required immunomodulatory treatment (IMT). Methotrexate (n = 44) and mycophenolate mofetil (n = 39) were the first agents after oral corticosteroids. 45% required addition of biologic agents (Adalimumab [n = 33], Infliximab [n = 8]). Younger age (p = 0.018), male sex (p = 0.011), and higher uveitis grade at presentation (p = 0.031) were associated with greater IMT ( ≥ 2) requirement. 53% had uveitis recurrence compared to 16% with nephritis recurrence. At the most recent visit, nephritis was controlled in 90%, while uveitis in 74%. Four (4%) patients required glaucoma surgery. Nine (8%) patients had renal complications., Conclusions: Most patients with TINU require steroid-sparing IMT for control of uveitis, with nearly half requiring addition of biologic agents. Urinalysis, urine β2M and SCr testing should be considered in children presenting with uveitis, especially when the disease is bilateral and anterior., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Retinitis pigmentosa (RP) is the leading cause of heritable retinal visual impairment. Clinically, it is characterized by a variable onset of progressive night blindness and visual field constriction. RP is characterized by wide genetic heterogeneity with a broad range of potential genes involved in the genesis of this disease. Very few cases have been reported of RP due to pathogenic variants in AGBL5 ., Materials and Methods: We report two patients with RP and bilallelic pathogenic variants in AGBL5 ., Results: Genetic sequencing showed one homozygous AGBL5 missense variant in one patient and a homozygous nonsense variant in the other. These patients presented with progressive peripheral vision loss and nyctalopia. Their RP phenotypes were similar to previous reports in literature., Conclusion: These two cases provide further evidence regarding the relationship of pathogenic variants in AGBL5 as a cause of autosomal recessive RP.

Background: Abusive head trauma (AHT) is frequently accompanied by dense/extensive retinal hemorrhages to the periphery with or without retinoschisis (complex retinal hemorrhages, cRH). cRH are uncommon without AHT or major trauma., Objective: The study objectives were to determine whether cRH are associated with inertial vs. contact mechanisms and are primary vs. secondary injuries., Participants and Setting: This retrospective study utilized a de-identified PediBIRN database of 701 children <3-years-old presenting to intensive care for head trauma. Children with motor vehicle related trauma and preexisting brain abnormalities were excluded. All had imaging showing head injury and a dedicated ophthalmology examination., Methods: Contact injuries included craniofacial soft tissue injuries, skull fractures and epidural hematoma. Inertial injuries included acute impairment or loss of consciousness and/or bilateral and/or interhemispheric subdural hemorrhage. Abuse was defined in two ways, by 1) predetermined criteria and 2) caretaking physicians/multidisciplinary team's diagnostic consensus., Results: PediBIRN subjects with cRH frequently experienced inertial injury (99.4 % (308/310, OR = 53.74 (16.91-170.77)) but infrequently isolated contact trauma (0.6 % (2/310), OR = 0.02 (0.0004-0.06)). Inertial injuries predominated over contact trauma among children with cRH sorted AHT by predetermined criteria (99.1 % (237/239), OR = 20.20 (6.09-67.01) vs 0.5 % (2/339), OR = 0.04 (0.01-0.17)). Fifty-nine percent of patients with cRH, <24 h altered consciousness, and inertial injuries lacked imaging evidence of brain hypoxia, ischemia, or swelling., Conclusions: cRH are significantly associated with inertial angular acceleration forces. They can occur without brain hypoxia, ischemia or swelling suggesting they are not secondary injuries., Competing Interests: Declaration of competing interest All authors except Adam Rockter have provided medical-legal consultations in cases of suspected child abuse., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to report a novel PRDM5 pathologic variant and ophthalmic findings in a family with 3 children diagnosed with brittle cornea syndrome (BCS). Histopathologic findings and surgical outcome of a child with BCS who underwent full-thickness corneal transplant are described., Methods: This is an observational case report of a nonconsanguineous Laotian family with 3 siblings diagnosed with BCS. Data collected included visual acuity, cycloplegic refraction, slit-lamp biomicroscopy, dilated fundus examination, corneal pachymetry, corneal topography, and general medical findings. Targeted testing through PRDM5 gene sequencing with copy number variation detection was conducted., Results: The 3 siblings included a 12-year-old boy and 8- and 6-year-old sisters, all of whom presented with myopia, blue-tinted sclerae, thin corneas, and variable corneal scarring. All 3 affected children were found to be homozygous for the PRDM5 gene variant c.1117&#95;1123delinsTTTAATGCTTACAAATGTTTG p.Asp373Phefs*57. Coding sequences of PRDM5 and ZNF469 genes were sequenced in their entirety, and this was the only pathologic variant present in this family. The youngest affected sister developed persistent hydrops with severely decreased vision and underwent penetrating keratoplasty. Histopathology revealed severe corneal thinning, diffuse absence of Bowman layer, and ruptured Descemet membrane scrolls., Conclusions: Three siblings with clinical signs of BCS, including corneal thinning, myopia, and blue sclerae, were found to have a novel PRDM5 gene pathologic variant. This pathologic variant has not been previously reported, although 1 downstream nonsense pathologic variant has been reported as pathogenic. The similar phenotypes in all affected patients support the pathogenicity of this variant. Surgical management of BCS presents unique challenges due to severe tissue fragility., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background/purpose: Mutations in CRB1 are associated with variable severity in expression leading to apparent phenotypic diversity. We present two retinal findings., Methods: We present two unrelated children with CRB1-related retinal dystrophy with a solitary mass visualized on fundoscopy. Both underwent a complete ophthalmologic examination including visual acuity assessment, optical coherence tomography, intravenous fluorescein angiography, and fundus autofluorescence., Results: In one child, a gliotic mass was observed on the superior temporal vessel away from disk. On optical coherence tomography, the mass appeared to be located in the superficial retina and contained discrete internal moth-eaten optically empty spaces as previously reported in the astrocytic hamartomas of tuberous sclerosis. Fundus autofluorescence showed speckled hyperautofluorescence of the lesion. In the other child, there was a calcified mass within the nerve fiber layer just temporal to the optic nerve. On optical coherence tomography, this mass appeared irregular in shape, encapsulated, and had a heterogeneous disorganized interior with hyperreflective areas., Conclusion: In this report, we detail two presentations of CRB1-related retinal dystrophy: retinal astrocytic hamartoma and another form of superficial retinal hamartoma. We believe this may represent a manifestation of CRB1 mutations. Recognition of this finding may prevent unnecessary evaluation for tumor cause in patients with CRB1-related retinal dystrophy.

Purpose: The retina-specific ABCA transporter, ABCA4, plays an essential role in translocating retinoids required by the visual cycle. ABCA4 genetic variants are known to cause a wide range of inherited retinal disorders, including Stargardt disease and cone-rod dystrophy. More than 1,400 ABCA4 missense variants have been identified; however, more than half of these remain variants of uncertain significance (VUS). The purpose of this study was to employ a predictive strategy to assess the pathogenicity of ABCA4 variants in inherited retinal diseases using protein modeling and computational approaches., Methods: We studied 13 clinically well-defined patients with ABCA4 retinopathies and identified the presence of 10 missense variants, including one novel variant in the ABCA4 gene, by next-generation sequencing (NGS). All variants were structurally analyzed using AlphaFold2 models and existing experimental structures of human ABCA4 protein. The results of these analyses were compared with patient clinical presentations to test the effectiveness of the methods employed in predicting variant pathogenicity., Results: We conducted a phenotype-genotype comparison of 13 genetically and phenotypically well-defined retinal disease patients. The in silico protein structure analyses we employed successfully detected the deleterious effect of missense variants found in this affected patient cohort. Our study provides American College of Medical Genetics and Genomics (ACMG)-defined supporting evidence of the pathogenicity of nine missense ABCA4 variants, aligning with the observed clinical phenotypes in this cohort., Conclusions: In this report, we describe a systematic approach to predicting the pathogenicity of ABCA4 variants by means of three-dimensional (3D) protein modeling and in silico structure analysis. Our results demonstrate concordance between disease severity and structural changes in protein models induced by genetic variations. Furthermore, the present study suggests that in silico protein structure analysis can be used as a predictor of pathogenicity and may facilitate the assessment of genetic VUS., (Copyright © 2023 Molecular Vision.)

Retinal hemorrhages in pediatric patients can be a diagnostic challenge for ophthalmologists. These hemorrhages can occur due to various underlying etiologies, including abusive head trauma, accidental trauma, and medical conditions. Accurate identification of the etiology is crucial for appropriate management and legal considerations. In recent years, deep learning techniques have shown promise in assisting healthcare professionals in making more accurate and timely diagnosis of a variety of disorders. We explore the potential of deep learning approaches for differentiating etiologies of pediatric retinal hemorrhages. Our study, which spanned multiple centers, analyzed 898 images, resulting in a final dataset of 597 retinal hemorrhage fundus photos categorized into medical (49.9%) and trauma (50.1%) etiologies. Deep learning models, specifically those based on ResNet and transformer architectures, were applied; FastViT-SA12, a hybrid transformer model, achieved the highest accuracy (90.55%) and area under the receiver operating characteristic curve (AUC) of 90.55%, while ResNet18 secured the highest sensitivity value (96.77%) on an independent test dataset. The study highlighted areas for optimization in artificial intelligence (AI) models specifically for pediatric retinal hemorrhages. While AI proves valuable in diagnosing these hemorrhages, the expertise of medical professionals remains irreplaceable. Collaborative efforts between AI specialists and pediatric ophthalmologists are crucial to fully harness AI's potential in diagnosing etiologies of pediatric retinal hemorrhages.

The anterior segment dysgeneses are a broad group of heterogeneous disorders characterized by developmental abnormalities of the anterior segment of the eye, including primary congenital aphakia, Peters sequence, aniridia, and Axenfeld-Rieger spectrum. These conditions can have overlapping phenotypes and both genotypic and phenotypic heterogeneity. This article provides a strategy for both phenotyping and then genotyping using a targeted stepwise approach., Competing Interests: The authors declare that there are no conflicts of interests of this paper., (Copyright: © 2023 Taiwan J Ophthalmol.)

We aimed to explore the delivery of pediatric genetic care before and during the COVID-19 pandemic and assess if disparities in care existed or emerged. We retrospectively reviewed the electronic medical record for patients 18 years old or younger seen in the Division of Pediatric Genetics between September 2019-March 2020 and April-October 2020. Outcomes included time between referral and new visit, recommendation and completion of genetic testing and/or follow-up visit within 6 months, and telemedicine versus in-person format. Outcomes were compared pre- and post-COVID-19 emergence across ethnicity, race, age, health insurance, socioeconomic status (SES), and use of medical interpretation services. Three hundred thirteen total records were reviewed with comparable demographics between cohorts. Cohort 2 had shorter times between referral and new visit, greater telemedicine utilization, and a greater proportion of testing completed. Younger patients tended to have shorter times between referral and initial visit. In Cohort 1, those with Medicaid insurance or no coverage had longer referral-initial visit times. In Cohort 2, there were differences in testing recommendation based on age. For all outcomes, no disparities were observed across ethnicity, race, SES, or use of medical interpretation services. This study characterizes the impact of the pandemic on pediatric genetics care delivery at our center and may have wider implications., (© 2023 Wiley Periodicals LLC.)

Background: Ophthalmic imaging plays an increasingly important role the evaluation of abusive head trauma, however these imaging modalities may be unfamiliar to non-ophthalmologists., Objective: To provide pediatricians and child abuse pediatric professionals with background on ophthalmic imaging techniques in the context of suspected abuse, as well as information on commercial options and costs for those interested in augmenting their ophthalmic imaging capabilities., Methods: We performed a review of the ophthalmic imaging literature for fundus photography, ocular coherence tomography, fluorescein angiography, ocular ultrasound, computed tomography, magnetic resonance imaging and postmortem imaging. We also contacted individual vendors for equipment pricing information., Results: For each ophthalmic imaging modality, we demonstrate its role in the evaluation of abusive head trauma including indications, potential findings, sensitivity and specificity of findings for abuse, and commercial options., Conclusions: Ophthalmic imaging is an important supportive component of the evaluation for abusive head trauma. When used in conjunction with clinical examination, ophthalmic imaging can improve diagnostic accuracy, support documentation, and possibly improve communication in medicolegal contexts., Competing Interests: Declaration of competing interest Dr. Levin has provided medicolegal expert consultation for both the defense and the prosecution or plaintiff in criminal and civil matters involving child abuse. The other authors have no relevant conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure . This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis., Competing Interests: J.L.W., A.M., and S.P. are coinventors on patent application 16/335,716 entitled “Drug-induced epigenetic remodeling to prevent fibrosis”., (© 2023 The Author(s).)

Purpose: To report clinical outcomes and risk factors for glaucoma in children and adolescents referred for increased cup:disk ratios (CDRs) to a tertiary referral center., Methods: This retrospective, single-center study examined all pediatric patients evaluated for increased CDR at Wills Eye Hospital. Patients who had previous known ocular disease were excluded. Demographic data, including sex, age, and race/ethnicity were recorded, as were baseline and follow-up ophthalmic examination findings, including intraocular pressure (IOP), CDR, diurnal curve, gonioscopy findings, and refractive error. Risks of glaucoma diagnosis based on these data were analyzed., Results: A total of 167 patients were included, of whom 6 were found to have glaucoma. Despite more than 2 years' follow-up on 61 patients, all glaucoma patients were identified within the first 3 months of evaluation. Baseline IOP was statistically significantly higher in glaucomatous patients than nonglaucomatous patients (28 ± 7 vs 15 ± 4, resp. [P = 0.0002]), as was maximum IOP on diurnal curve (24 ± 3 vs 17 ± 3 [P = 0.0005])., Conclusions: In our study cohort, diagnosis of glaucoma was apparent in the first year of evaluation. Baseline IOP and maximal IOP on diurnal curve were found to be statistically significantly associated with glaucoma diagnosis in pediatric patients referred for increased CDR., (Copyright © 2023 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Background: Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition., Methods: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses., Results: 128 individuals with causative variants in PITX2 or FOXC1 , including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1 -related ARS. Systemic anomalies were seen in all individuals with PITX2 -related ARS and the majority of those with FOXC1 -related ARS. PITX2 -related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1 -related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1 -related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS., Conclusion: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2 -related ARS or FOXC1 -related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy., Competing Interests: Competing interests: BW and GR are employees of GeneDx, Inc., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of this article is to determine the cause of Leber congenital amaurosis (LCA) in Chuuk state, Federated States of Micronesia (FSM). In this prospective observational case series, five patients with early-onset vision loss were examined in Chuuk state, FSM, during an ocular genetics visit to study the elevated incidence of microphthalmia. Because of their low vision these patients were incorrectly assumed to have microphthalmia. A complete ophthalmological exam established a clinical diagnosis of LCA. Candidate gene exons were sequenced with a targeted retinal dystrophy panel. Five subjects in three related families were diagnosed with LCA. All five were from Tonoas Island, within the Chuuk Lagoon, with ages ranging from 6 months to 16 years. DNA sequencing of affected individuals revealed a homozygous CRB1 NM&#95;201253.3:c.3134del pathogenic variant, which was heterozygous in their parents. CRB1 genotypes were confirmed by a PCR restriction assay. We report identification of a founder pathogenic variant in CRB1 responsible for autosomal recessive LCA in this isolated community. This discovery will lead to appropriate recurrence risk counseling., (© 2023 Wiley Periodicals LLC.)

Purpose: To assess the ocular health status of primary and secondary schoolchildren in Rwanda and to explore the use of the World Health Organization (WHO) primary eye care screening protocol., Methods: This was a cross-sectional population-based study across 19 schools in Rwanda. Initial screening was carried out using the WHO screening protocol, whereby visual acuity was measured using a tumbling E Snellen chart (6/60 and 6/12). Abnormal ocular features were identified using a flashlight and history against a checklist. All children with abnormal screening were referred to an on-site ophthalmic clinic for full examination. Those who could not be treated on-site were referred to an ophthalmologist at a hospital for specialist care., Results: A total of 24,892 children underwent ocular health screening. Of those, 1,865 (7.5%) failed the primary screening; 658 (2.6%) were false positives (35.3% of those who failed screening), and 1,207 (4.8%) true positives. The most frequently observed ocular diagnoses were allergic conjunctivitis (3.11%) and strabismus (0.26%). Refractive error was very rare (0.18%)., Conclusions: The WHO primary eye care curriculum provides existing health personnel with an approach to school-based vision screening that uses a standardized checklist and low-cost resources. In our study cohort, results indicated a low frequency of refractive error; the overwhelming majority of ocular problems could be identified on visual inspection., (Copyright © 2023. Published by Elsevier Inc.)

Importance: Familial exudative vitreoretinopathy (FEVR) is a nonsyndromic autosomal dominant retinal disorder commonly caused by variants in the FZD4 gene. This study investigates the potential role beyond ocular abnormalities for FZD4 gene variants in patients with FEVR., Objective: To evaluate the role of FZD4 in symptoms beyond those associated with FEVR through a patient with biallelic variants in FZD4., Design, Setting, and Participants: This case series included the DNA testing and phenotyping of 1 patient proband and her parents, combined with signaling assays, to determine the association of patient-derived compound heterozygous variants on FZD4 signaling and biologic function., Main Outcomes and Measures: FZD4 genes were tested using next-generation sequencing and Sanger sequencing. Cell-based assays measured the effect of the variants on FZD4 signaling., Results: The proband presented with absent red reflexes from complete tractional retinal detachments diagnosed at 3 days of age and failed the newborn screening hearing test. Auditory brainstem response at 6 months of age showed bilateral mild to moderate high-frequency sensorineural hearing loss. The patient manifested developmental delays in speech and walking. Intravenous fluorescein angiography (IVFA) of the patient's parents detected stage 1 FEVR. Genetic testing revealed 2 FZD4 variants in the patient, each variant found in 1 parent. Signaling assays confirmed that the presence of both variants was associated with significantly worse signaling activity compared with the heterozygous state., Conclusions and Relevance: Results of this case series suggest that extraocular syndromic FEVR was associated with FZD4 variants. The decrease in FZD4 signaling owing to the biallelic nature of the disease resulted in hearing deficits, developmental delays, and a more severe retinal phenotype.

Purpose: To examine the incidence of uveitis in children prescribed prostaglandin analogs (PGAs) for glaucoma., Methods: In this dual-center cohort study, the medical records of consecutive patients <18 years old treated with a PGA between January 1, 2012, and December 31, 2018, were reviewed retrospectively. Patients with all forms of glaucoma, including those with a prior history of uveitis, were included. Patients who had been on a PGA prior to their first recorded visit were excluded. Patient charts were reviewed for new or recurrent uveitis during the first year of PGA therapy., Results: A total of 103 children (147 eyes) were included, with a total PGA exposure of 1,352 child-months. Ninety-eight children (142 eyes) tolerated the PGA without an episode of uveitis. Five patients with a documented prior history of uveitis experienced a unilateral episode of uveitis. A review of their medical records identified prescribed or unscheduled decrease in topical steroids or immunosuppressive medication as the most likely cause of uveitis recurrence., Conclusions: This study provides further evidence that PGAs are unlikely to induce uveitis in children being treated for glaucoma and suggests that this may also be true in those with a history of uveitis. We are unable to evaluate whether PGAs make recurrence more likely or the tapering of steroids more difficult., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Background: Neurosurgical procedures may occur prior to eye examination in children with suspected abusive head trauma and raise questions by child abuse physicians and ophthalmologists regarding the contribution of neurosurgery to retinal hemorrhage found postoperatively. The purpose of this study was to determine the prevalence and patterns of retinal hemorrhage attributable to neurosurgical intervention in children., Methods: We conducted a retrospective cohort study of children undergoing neurosurgery who had postoperative ophthalmoscopy. Some children were also examined preoperatively. Primary outcome measures were the prevalence and patterns of retinal hemorrhage attributable to neurosurgical intervention. Medical records were reviewed to identify confounding coexistent diseases., Results: Among 267 children undergoing 289 neurosurgical procedures, there were no cases in which children had post-procedural retinal hemorrhage that could be attributed to neurosurgery. Retinal hemorrhage was seen in 32 (12%) cases, but in every case they were either already present on preoperative examination (13 cases) or matched the pattern of a coexistent known cause of retinal hemorrhage, including head trauma with unambiguous history and/or nonocular signs (13), hydrocephalus-related increased intracranial pressure with papilledema-associated peripapillary retinal hemorrhage (5), and retinopathy of prematurity ridge-associated retinal hemorrhage (1). No retinal hemorrhage could be attributed only to neurosurgery., Conclusions: Although children undergoing child abuse evaluations may have intracranial hemorrhage requiring neurosurgery that occurs before a dilated retinal examination can be performed, our data suggest that neurosurgery independently is unlikely to produce retinal hemorrhage and therefore is not a significant confounding factor in the interpretation of retinal hemorrhage patterns in child abuse evaluations., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Optic nerve aplasia (ONA) is a rare ocular anomaly. We report ophthalmologic, systemic, and genetic findings in ONA., Methods: Patients were identified through an International Pediatric Ophthalmology listserv and from the practice of the senior author. Participating Listserv physicians completed a data collection sheet. Children of all ages were included. Neuroimaging findings were also recorded., Results: Nine cases of ONA are reported. Patients' ages ranged from 10 days to 2 years (median 9 months). Seven cases were bilateral. All patients had absence of the optic nerve and retinal vessels in the affected eye or eyes. Ophthalmologic findings included glaucoma, microcornea, persistent pupillary membrane, iris coloboma, aniridia, retinal dysplasia, retinal atrophy, chorioretinal coloboma, and persistent fetal vasculature. Systemic findings included facial dysmorphism, cardiac, genitourinary, skeletal, and developmental defects. A BCOR mutation was found in one patient. One patient had rudimentary optic nerves and chiasm on imaging., Conclusion: ONA is a unilateral or bilateral condition that may be associated with anomalies of the anterior or posterior segment with or without systemic findings. Rudimentary optic nerve on neuroimaging in one case suggests that ONA is on the continuum of optic nerve hypoplasia., Competing Interests: A. V. Levin is supported by the Adeline Lutz—Steven S. T. Ching, MD. Distinguished Professorship in Ophthalmology and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology at the University of Rochester. The remaining authors report no conflict of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

Purpose: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism., Methods: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants., Results: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein., Conclusion: These studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition., Competing Interests: Conflict of Interest I.M.W is an employee of GeneDx, Inc. All other authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the natural history, management, and visual outcome in children with congenital primary aphakia (CPA)., Methods: This is a multicenter retrospective consecutive case series from five academic centers in England and North America., Results: A total of 27 eyes of 14 patients were included (male:female, 1.7:1). Thirteen patients had bilateral CPA, and 1 patient had unilateral CPA. Mean age at diagnosis was 18 months (median, 21; range, 0.5-144). Of 11 patients who underwent genetic testing, 9 had FOXE3 pathogenic variants. In all patients, visual acuity at presentation was not better than fixing and following light. Typical findings included silvery appearance of the cornea with vascularization (96%), glaucoma (81%), iridocorneal adhesions (74%), optic nerve coloboma (55%), abnormal vitreous (33%), retinal detachment (30%), and aniridia with hypoplasia of ciliary body (19%). Surgical interventions in select patients included penetrating keratoplasty (PKP), glaucoma drainage device implantation, and cyclophotocoagulation (CPC)., Conclusions: Eyes with corneal ectasia and a silvery appearance of the cornea with vascularization should alert the physician to the possibility of CPA. Glaucoma causes globe enlargement and may increase the risk of corneal perforation, but glaucoma is often refractory to medical treatment, and the threshold for surgical treatment should be low. PKP outcomes are very poor., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. All rights reserved.)

In today's complex media environment, does media coverage influence youth and young adults' (YYA) tobacco use and intentions? We conceptualize the "public communication environment" and effect mediators, then ask whether over time variation in exogenously measured tobacco media coverage from mass and social media sources predicts daily YYA cigarette smoking intentions measured in a rolling nationally representative phone survey (N = 11,847 on 1,147 days between May 2014 and June 2017). Past week anti-tobacco and pro-tobacco content from Twitter, newspapers, broadcast news, Associated Press, and web blogs made coherent scales (thetas = 0.77 and 0.79). Opportunities for exposure to anti-tobacco content in the past week predicted lower intentions to smoke (Odds ratio [OR] = 0.95, p < .05, 95% confidence interval [CI] = 0.91-1.00). The effect was stronger among current smokers than among nonsmokers (interaction OR = 0.88, p < .05, 95% CI = 0.77-1.00). These findings support specific effects of anti-tobacco media coverage and illustrate a productive general approach to conceptualizing and assessing effects in the complex media environment., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Communication Association.)

Media coverage can impact support for health policies and, ultimately, compliance with those policies. Prior research found consistent, high support for Tobacco 21 policies, which raise the minimum legal age of tobacco purchase to 21, among adults and nonsmoking youth. However, a recent study found support (i.e., agreement with the statement: "The legal age to buy tobacco cigarettes should be increased from 18 to 21") among 13-20-year-old smokers increased from 2014 until mid-2016 and then declined steadily through mid-2017. To assess whether media coverage could be related to young smokers' changing support, we conducted an exploratory content analysis to identify texts about Tobacco 21 in a large corpus of tobacco texts (N = 135,691) published in four popular media sources from 2014 to 2017. For this content analysis, we developed a novel methodological approach that combined supervised and unsupervised machine learning methods and could be useful in other areas of communication research. We found that the prevalence of Tobacco 21 media coverage and Tobacco 21 support among young smokers exhibited similar temporal patterns for much of the study period. These findings highlight the need for continued research into the effects of media coverage on Tobacco 21 support among young smokers, a group that must comply with Tobacco 21 policies in order to ensure maximum effectiveness. This research is of particular utility following the 2019 passage of a federal Tobacco 21 regulation, as the public health impact of this regulation could be limited by low public support, and thus low rates of policy compliance.

The forkhead transcription factor FOXE3 is critical for vertebrate eye development. Recessive and dominant variants cause human ocular disease but the full range of phenotypes and mechanisms of action for the two classes of variants are unknown. We identified FOXE3 variants in individuals with congenital eye malformations and carried out in vitro functional analysis on selected alleles. Sixteen new recessive and dominant families, including six novel variants, were identified. Analysis of new and previously reported genetic and clinical data demonstrated a broad phenotypic range with an overlap between recessive and dominant disease. Most families with recessive alleles, composed of truncating and forkhead-domain missense variants, had severe corneal opacity (90%; sclerocornea in 47%), aphakia (83%) and microphthalmia (80%), but some had milder features including isolated cataract. The phenotype was most variable for recessive missense variants, suggesting that the functional consequences may be highly dependent on the type of amino acid substitution and its position. When assessed, aniridia or iris hypoplasia were noted in 89% and optic nerve anomalies in 60% of recessive cases, indicating that these defects are also common and may be underrecognized. In dominant pedigrees, caused by extension variants, normal eye size (96%), cataracts (99%) and variable anterior segment anomalies were seen in most, but some individuals had microphthalmia, aphakia or sclerocornea, more typical of recessive disease. Functional studies identified variable effects on the protein stability, DNA binding, nuclear localization and transcriptional activity for recessive FOXE3 variants, whereas dominant alleles showed severe impairment in all areas and dominant-negative characteristics., (© The Author(s) 2021. Published by Oxford University Press.)

Gillespie syndrome (GLSP) is characterized by bilateral symmetric partial aplasia of the iris presenting as a fixed and large pupil, cerebellar hypoplasia with ataxia, congenital hypotonia, and varying levels of intellectual disability. GLSP is caused by either biallelic or heterozygous, dominant-negative, pathogenic variants in ITPR1. Here, we present a 5-year-old male with GLSP who was found to have a heterozygous, de novo intronic variant in ITPR1 (NM&#95;001168272.1:c.5935-17G > A) through genome sequencing (GS). Sanger sequencing of cDNA from this individual's fibroblasts showed the retention of 15 nucleotides from intron 45, which is predicted to cause an in-frame insertion of five amino acids near the C-terminal transmembrane domain of ITPR1. In addition, qPCR and cDNA sequencing demonstrated reduced expression of both ITPR1 alleles in fibroblasts when compared to parental samples. Given the close proximity of the predicted in-frame amino acid insertion to the site of previously described heterozygous, de novo, dominant-negative, pathogenic variants in GLSP, we predict that this variant also has a dominant-negative effect on ITPR1 channel function. Overall, this is the first report of a de novo intronic variant causing GLSP, which emphasizes the utility of GS and cDNA studies for diagnosing patients with a clinical presentation of GLSP and negative clinical exome sequencing., (© 2021 Wiley Periodicals LLC.)

Background: The characteristic findings of abusive head trauma (AHT) include retinal hemorrhages (RH). RH have many etiologies in childhood, which should be considered in the differential diagnosis of possible child abuse. The relationship between RH and thrombophilia in children is not well established., Objective: In this literature review, we sought to assess whether retinal findings in pediatric patients with thrombophilia could mimic those of AHT., Methods: A literature search was performed to identify all cases of thrombophilia in children less than 18 years old with ocular manifestations. Disorders of thrombophilia including protein C and S deficiency, factor V Leiden (FVL), prothrombin variant, MTHFR mutation, hyperhomocysteinemia, elevated factor VIII, and elevated lipoprotein (a) were considered. All cases of pediatric thrombophilia with retinal examination or intraocular bleeding were included. If provided, descriptions of the RH were reviewed., Results: Our initial search yielded 514 results. Forty-three articles met our inclusion criteria. We identified 3 children with RH within the AHT usual age range (<5 years old), ages 5 weeks and 7 weeks old, in the setting of thrombophilia. One child had ocular findings that could potentially mimic abuse. No other indicators of abuse were present in this case., Conclusions: Based on previous reports, thrombophilia alone has not been shown to clearly mimic abusive head trauma. In reported cases of thrombophilia with RH, the clinical picture and ophthalmic findings are usually distinct from abuse., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: We previously reported costs and outcomes of the Children's Eye Care Adherence Program (CECAP1), a social worker intervention designed to improve adherence to eye care for underserved children in urban Philadelphia. Using cost findings from CECAP1, we revised the intervention to reduce costs. The aim of this study was to evaluate costs and effectiveness of the revised intervention (CECAP2)., Design: Retrospective cohort study., Methods: Records of children needing ophthalmic follow-up after 2 community-based vision screening programs were reviewed. We modified CECAP1 to prioritize children more likely to visit, decreased phone calls and scheduling attempts, better documented children already followed by other doctors, and constricted our geographic catchment area for better accessibility. Cost was calculated using time spent executing CECAP2 by our salaried social worker. Effectiveness was defined as the percentage of patients completing at least 1 follow-up visit within the recommended time frame., Results: Of 462 children referred to CECAP2 from our in-school and on-campus screening programs, 242 (52.4%) completed subsequent recommended eye examinations, a proportion identical to our prior report (52.3%). Social worker time per patient was 0.8 hours; a significant reduction from the previous 2.6 hours (P < .01). Cost per patient was $32.73; a significant reduction compared to the previous $77.20 (P < .01)., Conclusions: Programmatic changes to reduce social worker intervention time and target potential patients by likelihood to attend along with constriction of the catchment area led to reduced costs by more than 50%, without impairing CECAP effectiveness., (Copyright © 2021 Elsevier Inc. All rights reserved.)