Periocular ecthyma gangrenosum with Pseudomonas septicemia in an infant: A case report.

Ecthyma gangrenosum is a skin manifestation of fatal septicemia. We report a case of periocular ecthyma gangrenosum, which is an uncommonly infected area and rarely reported in infants. A 1-month-old female infant with periocular ecthyma gangrenosum presented with a high-grade fever and acute left medial canthus of the eyelid swelling and erythema. Hemoculture at 6 h confirmed Pseudomonas aeruginosa infection. Intravenous and topical antibiotics were administered. Daily dressing of the wound and noninvasive bedside escharectomy were performed. Cosmetically acceptable scar was achieved without additional surgery. The patient was considered to have congenital neutropenia due to persistent neutropenia and severe skin and mucosal infections in her first year of life. Noninvasive debridement of the wound reduces the risk of exposure keratitis, lacrimal drainage pathway damage, and the need for further surgical reconstruction. The cause of compromised immunity in infants with ecthyma gangrenosum should be investigated, and intensive follow-up is recommended.

Digital Gangrene and Antiphospholipid Syndrome in a Retinoblastoma Patient with Chromosome 13q Deletion: A Case Report.

A 19-month-old girl with Cornelia de Lange-like dysmorphic features presented with left eye leukocoria. She was diagnosed with 13q deletion retinoblastoma grade 4 with high-risk features and bone marrow involvement. She underwent enucleation, and the first course of intravenous chemotherapy was initiated. On day 10 after the first chemotherapy dose, she developed digital gangrene of her left hand. She was diagnosed with acute artery occlusion and limb ischemia. Thrombophilia work-up revealed antiphospholipid antibodies, and paraneoplastic syndrome is another possible cause of digital gangrene. The patient's left thumb and index finger were amputated. After 1 month of hospitalization, she was discharged. Before the second course of chemotherapy, the patient died of systemic metastatic retinoblastoma with respiratory failure due to pneumonia. Our postulation of the mechanism for digital gangrene was the combination of chemotherapy, paraneoplastic syndrome, and antiphospholipid syndrome. Digital gangrene could be a poor prognostic indicator in patients with retinoblastoma.

Protein modeling and in silico analysis to assess pathogenicity of ABCA4 variants in patients with inherited retinal disease.

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.

Correlation between clinical presentations, radiological findings and high risk histopathological features of primary enucleated eyes with advanced retinoblastoma at Queen Sirikit National Institute of Child Health: 5 years result.

PURPOSE: To evaluate the correlation between clinical presentations, radiological findings and high risk histopathological features of primary enucleated eyes in patients with advanced retinoblastoma at a tertiary child hospital in Thailand. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who were treated with primary enucleation of tumor eyes between 2015-2020. Demographic data, radiological assessment, and histopathological findings were collected. The association between clinical presentations and high-risk histopathological features in the primary enucleated eyes were evaluated. The radiological findings, which showed characteristic of high risk features, were compared with the histopathological findings. RESULTS: Thirty-three enucleated eyes were enrolled in this study. The mean age at diagnosis was 23.12 months. Most patients had unilateral group E retinoblastoma, with no difference in sex and laterality of the eye. Leukocoria was the most common presentation, followed by proptosis and uveitis. Older age at presentation were statistically associated with post laminar cribrosa optic nerve invasion (P-value 0.0027) and high-risk histopathological features in enucleated eyes (P-value 0.0032). Clinical presentations with proptosis were statistically associated with post laminar cribrosa optic nerve invasion, while leukocoria and uveitis were statistically associated with anterior segment invasion. Unifocal intraocular mass with necrosis was the most common histopathological finding. High-risk features were found in 45% of primary enucleated eye. The sensitivity and specificity of magnetic resonance imaging (MRI) for detected optic nerve invasion in retinoblastoma patients were 75% and 54%, respectively. CONCLUSION: Patients with unilateral retinoblastoma who presented with older age related to high-risk features after enucleation. Ophthalmic examination with slitlamp is the best way for detection of anterior segment invasion. Choroidal invasion was unable to predict with clinical presentation. MRI was the better imaging for detection of post laminar cribrosa optic nerve invasion.

Cryptophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation.

FREM2 is a member of the FREM2-FRAS1-FREM1 protein complex which contributes to epithelial-mesenchymal coupling. We report a Thai woman with cryptophthalmos, dental anomalies, and oral vestibule defect. A compound heterozygous mutation (c.6499C>T; p.Arg2167Trp and c.641_642del; p.Glu214GlyfsTer135) in the FREM2 gene was identified. The frameshift variant p.Glu214GlyfsTer135 is de novo and novel. It is predicted to result in the loss of most of the functional domains. The p.Arg2167Trp mutation was predicted to disrupt both Ca2+ binding and conformational change. The Arg2167Trp mutant protein has been shown to cause partial loss of function, decrease its interaction with FREM1 and result in impaired function of the FRAS1-FREM2-FREM1 complex. Frem2 was shown to be expressed in the developing tooth and vestibular lamina. It is hypothesized that these mutations resulted in aberration of the FRAS1-FREM2-FREM1 protein complex, resulting in loss of nephronectin, basement membrane disruption, and abnormal epithelial-mesenchymal interactions leading to dental and oral vestibule malformations.

Prevalence of Prescription Glasses in the First-Grade Thai Students (7-8 Years Old).

PURPOSE: To study the prevalence of the prescription glasses given to first-grade students due to the "Good Sight for Thai Children" (GSTC) policy. METHODS: This was a cross-sectional study that examined all prescription glasses given to first-grade students throughout Thailand, after visual screening due to the GSTC policy between 2016 and 2017. Trained class teachers screened their students' visual acuity and referred children who had less than 20/40 visual acuity in either eye to a hospital for an eye examination and prescription glasses. RESULTS: A total of 786,729 students were screened. Of these, 20,401 (2.59%) students were referred to hospital. However, only 9867 (48.37%) students presented to a hospital. Glasses were prescribed for 5324 (53.96%) students following cycloplegic refraction by ophthalmologists or trained refractionists. The mean spherical equivalent was -1.08 (-19.00 to +10.00, SD 2.32) diopters. There were 1626 (30.54%) children at amblyopic risk without glasses. A 5.49% had high myopia (< -6 diopters), 5.22% had high hyperopia (> +5 diopters) and 27.82% had high astigmatism (>2 diopters). A cylindrical lens analysis showed that 81.53% had with-the-rule astigmatism, 4.07% had against-the-rule astigmatism, and 14.40% had oblique astigmatism. CONCLUSION: Although the reliable prevalence of refractive error cannot be estimated, the prevalence of visual impairment may be estimated. There were a number of students who required glasses. The astigmatism was the most common refractive error on prescription glasses for first-grade children. With-the-rule astigmatism was the most prevalent. The visual screening program of school children proved to be valuable and should be continued and developed.

Outcomes of pediatric accommodative esotropia with botulinum toxin A treatment in Thailand.

Accommodative esotropia is a condition commonly encountered by pediatric ophthalmologists. Patient with accommodative esotropia wear hyperopic glasses to decrease accommodation which occasionally provide them with good vision without glasses. Children are known to have limited compliance with glasses and patching. Their limited cooperation can also lead to variability in angle measurement across visits and defer surgery. To cope with these challenges, our team offered botulinum toxin injection to the medial rectus as an optional treatment while waiting for compliance and deferring the surgery. This is retrospective study including data from 114 accommodative esotropia patients who were injected with botulinum toxin into the medial rectus between 2010 and 2017. Of these, 102 patients met the inclusion criteria. Almost half of the patients were boys (47.06%). The average angle deviation before injection was 40 prism diopters (PD). The post-injection angle averaged at 11 PD at 2 weeks, 19 PD at 3 months, and 25 PD at 6 months. At 6 months, 51 patients (50.00%) had satisfactory results, 17 (16.67%) had excellent results (ortho to esotropia < 10 PD) and 34 (33.33%) had small angle esotropia (esotropia 11-20 PD). All complications including ptosis (37.25%), exotropia (11.76%), and hypertropia (4.9%) were reversible. Botulinum toxin injection into the medial rectus for pediatric esotropia showed satisfactory outcomes in 50% of patients with minimal complications. The study showed no significant association of good outcomes with age at onset, age during injection, status of development, status of amblyopia, refractive error, and angle of deviation as analyzed by the statistical package for social sciences.

Optical Coherence Tomography in Knobloch Syndrome.

BACKGROUND AND OBJECTIVE: Knobloch syndrome is a genetic disorder defined by occipital defect, high myopia, and vitreoretinal degeneration. The authors studied retinal changes in patients with Knobloch syndrome using optical coherence tomography (OCT). PATIENTS AND METHODS: The authors report patients with Knobloch syndrome who received OCT testing during their care from 2011 to 2016. Diagnosis was based on high myopia, characteristic fundus, and occipital scalp or skull abnormalities with/without featureless irides and/or ectopia lentis. When available, diagnosis was confirmed by the detection of COL18A1 mutations. RESULTS: The authors studied eight eyes from five patients. Two eyes were excluded due to chronic retinal detachment. OCT findings included epiretinal membrane, peripapillary vitreoretinal traction with retinoschisis, absent or rudimentary foveal pits, mean macular thickness of 113.4 µm, poor lamination, retinal pigment epithelium (RPE) atrophy, photoreceptor depletion, and mean choroidal thickness of 168.5 µm with enlarged choroidal vessels. CONCLUSION: OCT findings in Knobloch syndrome include abnormal vitreoretinal traction, poor foveal differentiation, poor retinal lamination, retinal thinning, RPE attenuation, myopic choroidal thinning, and pachychoroid. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e203-e210.].

Evaluation of a Free Public Smartphone Application to Detect Leukocoria in High-Risk Children Aged 1 to 6 Years.

PURPOSE: To determine whether a white-eye detector smartphone application (app) can be used as a screening tool to detect early signs of leukocoria in a clinical practice. METHODS: A prospective, single-visit study of children aged 1 to 6 years presenting to the University Eye Clinic of Genova for a complete pediatric ophthalmologic examination was conducted. All children who met the enrollment criteria were screened by an orthoptist with the CRADLE (Computer Assisted Detector of Leukocoria) smartphone app for an iPhone operating system (iOS) (iPhone 7; Apple, Cupertino, CA). Cycloplegic retinoscopy and fundus examination were performed 30 minutes after one to two drops of a pediatric combination drop, comprising tropicamide 1% and phenylephrine 2.5%, were instilled. A comparison between the two methods yielded sensitivity, specificity, and negative likelihood ratio values. RESULTS: A total of 244 eyes of 122 children were included in the study. Nine eyes of 244 (3.6%) had leukocoria evaluable by penlight caused by amblyogenic cataract, 1 (0.4%) patient had retinopathy of prematurity stage 5, and 3 (1.2%) patients had retinoblastoma. The sensitivity of the white-eye detector app was 15.38% (95% confidence interval [CI]: 1.92% to 45.45%), the specificity was 100% (95% CI: 98.48% to 100.00%), and the negative likelihood ratio was 0.85 (95% CI: 0.67 to 1.07). CONCLUSIONS: A smartphone photoscreening app able to detect leukocoria may provide valuable support for children's parents. However, it cannot be considered an alternative to the ophthalmoscope for children. [J Pediatr Ophthalmol Strabismus. 2019;56(4):229-232.].

Ophthalmic manifestations of Heimler syndrome due to PEX6 mutations.

BACKGROUND/AIMS: Pigmentary retinal dystrophy and macular dystrophy have been previously reported in Heimler syndrome due to mutations in PEX1. Here we reported the ocular manifestations in Heimler syndrome due to mutations in PEX6. MATERIALS AND METHODS: Medical records were reviewed to identify patient demographics, ophthalmic and systemic findings, and results of diagnostic testing including whole genome sequencing. RESULTS: Patient 1 is 12-year-old boy with a novel mutation c.275T>G (p.Val92Gly) and known mutation c.1802G>A (p.Arg601Gln) in PEX6. Patient 2 is a 7-year-old girl with the same known c.1802G>A (p.Arg601Gln) mutation and another novel missense mutation c.296G>T (p.Arg99Leu). Both patients exhibited a pigmentary retinopathy. Visual acuity in patient 1 was 20/80 and 20/25 following treatment of intraretinal cystoid spaces with carbonic anhydrase inhibitors, while patient 2 had visual acuity of 20/20 in both eyes without intraretinal cysts. Fundus autofluorescence showed a multitude of hyperfluorescent deposits in the paramacular area of both eyes. OCTs revealed significant depletion of photoreceptors in both patients and macular intraretinal cystoid spaces in one patient. Full field electroretinograms showed normal or abnormal photopic but normal scotopic responses. Multifocal electroretinograms were abnormal. CONCLUSIONS: Heimler syndrome due to biallelic PEX6 mutations demonstrates a macular dystrophy with characteristic fundus autofluorescence and may be complicated by intraretinal cystoid spaces.

Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing.

PURPOSE: Mutations in the ABCA4 gene result in a broad spectrum of severe retinal degeneration, including Stargardt macular dystrophy, fundus flavimaculatus, autosomal recessive retinitis pigmentosa, and cone-rod dystrophy. In addition to the detection of well-characterized mutations, genetic testing frequently yields novel variants of unknown significance. The purpose of this report is to describe an approach to aid in the assessment of genetic variants of unknown significance. CASE REPORT: We report an 11-year-old girl with Stargardt disease harboring novel compound heterozygous deletions of ABCA4 (c.850_857delATTCAAGA and c.6184_6187delGTCT). The pathogenicity of these variants was otherwise unknown. Both deletions introduce premature stop codons and are localized within the open reading frame of ABCA4. The c.850_857delATTCAAGA occurs early in the gene and leads to a significantly truncated protein of only 317 amino acids. The c.6184_6187delGTCT, is localized to the 3' terminus of the ORF and results in removal of the last 161 out of 2,273 amino acids of ABCA4, including the VFVNFA motif, which has been shown to be critical in ABCA4 protein function. Homology-based protein modeling of ABCA4 harboring this deletion suggests significant alterations in the protein structure and function. CONCLUSIONS: Our analyses allowed us to classify novel variants in ABCA4 as being clearly loss-of-function mutations, and thus pathogenic variants. In cases of variants of unknown significance, appraising the protein structure-function consequences of genetic mutations using in silico tools may help to predict the clinical importance of variants of uncertain pathogenicity.