ABSTRACT
CHARGE syndrome is a rare multi-system condition associated with CHD7 variants. However, ocular manifestations and particularly ophthalmic genotype-phenotype associations, are not well-studied. This study evaluated ocular manifestations and genotype-phenotype associations in pediatric patients with CHARGE syndrome. A retrospective chart review included pediatric patients under 20 years-old with clinical diagnosis of CHARGE syndrome and documented ophthalmic examination. Demographics, genetic testing, and ocular findings were collected. Comprehensive literature review enhanced the genotype-phenotype analysis. Forty-two patients (20 male) underwent eye examination at an average age of 9.45 ± 6.52 years-old. Thirty-nine (93%) had ophthalmic manifestations in at least one eye. Optic nerve/chorioretinal colobomas were most common (38 patients), followed by microphthalmia (13), cataract (6), and iris colobomas (4). Extraocular findings included strabismus (32 patients), nasolacrimal duct obstructions (11, 5 with punctal agenesis), and cranial nerve VII palsy (10). Genotype-phenotype analyses (27 patients) showed variability in ocular phenotypes without association to location or variant types. Splicing (10 patients) and frameshift (10) variants were most prevalent. Patients with CHARGE syndrome may present with a myriad of ophthalmic manifestations. There is limited data regarding genotype-phenotype correlations and additional studies are needed.
Subject(s)
CHARGE Syndrome , Genetic Association Studies , Phenotype , Humans , CHARGE Syndrome/genetics , CHARGE Syndrome/pathology , CHARGE Syndrome/diagnosis , Male , Child , Female , Child, Preschool , Adolescent , Coloboma/genetics , Coloboma/pathology , Infant , Genotype , Mutation/genetics , Retrospective Studies , DNA-Binding Proteins/genetics , DNA Helicases/genetics , Cataract/genetics , Cataract/pathology , Young AdultABSTRACT
BACKGROUND: Determine outcomes of concurrent strabismus surgery with placement of a glaucoma drainage device (GDD) in children. METHODS: Retrospective review of pediatric patients who underwent simultaneous lateral rectus (LR) muscle surgery with superotemporal GDD placement. Strabismus and GDD success were defined as residual horizontal misalignment < 10 prism diopter (PD) and intraocular pressure (IOP) < 21 mmHg, no visually devastating complications, and no additional IOP-lowering surgeries. RESULTS: Fifteen eyes of 13 patients (69% male) underwent LR surgery (14 recessions, 1 resection) for exotropia or esotropia simultaneous with GDD placement (13 Baerveldt, 2 Ahmed) at 8.34 ± 5.26 years. Preoperative visual acuity (VA) in operative eye (0.89 ± 0.54) was worse than non-operative eye (0.23 ± 0.44, p = 0.0032). Preoperative horizontal deviation was 38.3 ± 9.4 PD and LR recession was 7.4 ± 1.1 mm. At final follow-up, VA in operative eye (0.87 ± 0.52) was unchanged from preoperative (p = 0.4062). Final IOP was significantly decreased (12.4 ± 4.7 mmHg vs. 31.1 ± 11.4 mmHg, p = 0.0001) as was number of glaucoma medications (2.7 ± 1.7 vs. 1.1 ± 1.3, p = 0.0037). Five (38%) and 9 patients (69%) met criteria for strabismus and GDD success, respectively. Two eyes required tube revision and endoscopic cyclophotocoagulation and 2 eyes had additional strabismus surgery. CONCLUSIONS: Concurrent strabismus and GDD surgery decreased horizontal deviation and obtained IOP control. It is important to consider correction of strabismus at time of GDD placement to maximize visual development and improve cosmesis in children with glaucoma.
Subject(s)
Glaucoma Drainage Implants , Glaucoma , Strabismus , Humans , Male , Child , Female , Treatment Outcome , Glaucoma/complications , Glaucoma/surgery , Intraocular Pressure , Prosthesis Implantation , Strabismus/surgery , Retrospective Studies , Follow-Up StudiesABSTRACT
BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.
Subject(s)
Exanthema , Glaucoma, Open-Angle , Odontodysplasia , DEAD Box Protein 58/genetics , Exanthema/pathology , Glaucoma, Open-Angle/pathology , Humans , Interferons/genetics , Metacarpus/pathology , Odontodysplasia/genetics , Odontodysplasia/pathology , Receptors, ImmunologicABSTRACT
BACKGROUND: There is no consensus and few reports as to the surgical management of encapsulated Ahmed glaucoma drainage devices (GDD) which no longer control intraocular pressure (IOP), especially within the pediatric population. The purpose of this study was to report outcomes of exchanging the Ahmed GDD for a Baerveldt GDD in children with refractory glaucoma. METHODS: Retrospective review of children (< 18yrs) who underwent removal of Ahmed FP7 and placement of Baerveldt 350 (2016-2021) with ≥ 3-month follow-up. Surgical success was defined as IOP 5-20 mmHg without additional IOP-lowering surgeries or visually devastating complications. Outcomes included change in best-corrected visual acuity (BCVA), intraocular pressure (IOP), and number of glaucoma medications. RESULTS: Twelve eyes of 10 patients underwent superotemporal Ahmed FP7 to Baerveldt 350 GDD exchange at 8.8 ± 3.6 years. Time to Ahmed failure was 2.7 ± 1.9 years with 1-, 3-, and 5-year survival rates of 83% with a 95% CI[48,95], 33% with a 95% CI[10, 59], and 8% with a 95% CI[0, 30]. At final follow-up (2.5 ± 1.8 years), success rate for Baerveldt 350 GDDs was 75% (9 of 12 eyes) with 1 and 3-yr survival rates of 100% and 71% with 95% CI[25,92], respectively. IOP (24.1 ± 2.9 vs. 14.9 ± 3.1 mmHg) and number of glaucoma medications (3.7 ± 0.7 vs. 2.7 ± 1.1) were significantly decreased (p < 0.004). BCVA remained stable. Two eyes required cycloablation and 1 eye developed a retinal detachment. CONCLUSIONS: Ahmed removal with Baerveldt placement can improve IOP control with fewer medications in cases of refractory pediatric glaucoma. However, more eyes with greater follow-up are required to determine long-term outcomes.
Subject(s)
Glaucoma Drainage Implants , Glaucoma , Humans , Child , Eye , Glaucoma/surgery , Tonometry, Ocular , Intraocular PressureABSTRACT
Combined pituitary hormone deficiency (CPHD) is a genetically heterogeneous disorder caused by mutations in over 30 genes. The loss-of-function mutations in many of these genes, including orthodenticle homeobox 2 (OTX2), can present with a broad range of clinical symptoms, which provides a challenge for predicting phenotype from genotype. Another challenge in human genetics is functional evaluation of rare genetic variants that are predicted to be deleterious. Zebrafish are an excellent vertebrate model for evaluating gene function and disease pathogenesis, especially because large numbers of progeny can be obtained, overcoming the challenge of individual variation. To clarify the utility of zebrafish for the analysis of CPHD-related genes, we analyzed the effect of OTX2 loss of function in zebrafish. The otx2b gene is expressed in the developing hypothalamus, and otx2bhu3625/hu3625 fish exhibit multiple defects in the development of head structures and are not viable past 10 days post fertilization (dpf). Otx2bhu3625/hu3625 fish have a small hypothalamus and low expression of pituitary growth hormone and prolactin (prl). The gills of otx2bhu3625/hu3625 fish have weak sodium influx, consistent with the role of prolactin in osmoregulation. The otx2bhu3625/hu3625 eyes are microphthalmic with colobomas, which may underlie the inability of the mutant fish to find food. The small pituitary and eyes are associated with reduced cell proliferation and increased apoptosis evident at 3 and 5 dpf, respectively. These observations establish the zebrafish as a useful tool for the analysis of CPHD genes with variable and complex phenotypes.
Subject(s)
Growth Hormone/genetics , Hypopituitarism/genetics , Otx Transcription Factors/genetics , Zebrafish Proteins/genetics , Animals , Apoptosis/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Developmental/genetics , Gills/metabolism , Gills/pathology , Humans , Hypopituitarism/pathology , Hypothalamus/growth & development , Hypothalamus/pathology , Loss of Function Mutation/genetics , Mandible/pathology , Prolactin/genetics , Zebrafish/geneticsABSTRACT
BACKGROUND: Evaluate outcomes and identify prognostic factors in congenital aniridia. METHODS: Retrospective interventional case series of patients with congenital aniridia treated between 2012-2020. Ocular examination and surgical details were collected. Surgical failure was defined as disease progression or need for additional surgery for same/related indication. Kaplan-Meier survival curves, Wilcoxon test, and univariate and multivariate linear regression analyses were performed. RESULTS: Ninety-four patients with congenital aniridia presented at median 19.0 years. Two-thirds of patients underwent ≥ 1intraocular surgery, with average of 1.7 ± 2.3 surgeries/eye. At final follow-up (median 4.0 years), 45% of eyes had undergone lensectomy. Aphakic eyes showed worse visual acuity (VA) than phakic or pseudophakic eyes. Glaucoma affected 52% of eyes, of which half required IOP-lowering surgery. Glaucoma drainage devices showed the highest success rate (71%) at 14.2 ± 15.4 years of follow-up. Keratopathy affected 65% of eyes and one-third underwent corneal surgery. Keratoprosthesis had the longest survival rates at 10-years (64% with 95% CI [32,84]). LogMAR VA at presentation and final follow-up were not statistically different. Half of patients were legally blind at final follow-up. Final VA was associated with presenting VA, glaucoma diagnosis, and cataract or keratopathy at presentation. Penetrating keratoplasty and keratoprosthesis implantation correlated with worse BCVA. CONCLUSIONS: Most aniridic patients in this large US-based cohort underwent at least 1 intraocular surgery. Cataract, glaucoma, and keratopathy were associated with worse VA and are important prognostic factors to consider when managing congenital aniridia.
Subject(s)
Aniridia , Cataract , Corneal Diseases , Glaucoma Drainage Implants , Glaucoma , Aniridia/complications , Aniridia/diagnosis , Aniridia/surgery , Cataract/complications , Cornea , Corneal Diseases/surgery , Follow-Up Studies , Glaucoma/complications , Glaucoma/diagnosis , Glaucoma/surgery , Humans , Intraocular Pressure , Prognosis , Retrospective Studies , Treatment Outcome , Vision DisordersABSTRACT
BACKGROUND: Limited data exists on the effectiveness of the collagen matrix, Ologen, on increasing Ahmed glaucoma valve (AGV) success in childhood glaucomas. METHODS: Ocular examination and surgical details of pediatric patients who underwent AGV placement ± Ologen augmentation between 2012 and 2020. Complete success was defined as intraocular pressure (IOP) between 5 and 20 mmHg without glaucoma medications and additional IOP-lowering surgeries. Qualified success was defined as above, except IOP control maintained with or without glaucoma medications. RESULTS: Twenty-two eyes of 16 patients underwent AGV placement of which 6 eyes had Ologen-augmentation (OAGV) and 16 eyes had conventional surgery (CAGV). Average age was 6.4 ± 5.1 years with 4.2 ± 2.5 follow-up years. There was no difference in age, number of previous surgeries, and preoperative IOP and glaucoma medications. At final follow-up, success rate was 100% (5 eyes complete, 6 eyes qualified) in the OAGV group compared to 31% (0 eyes complete, 5 eyes qualified) in the CAGV group. One and two-year survival rates were 100% for OAGV compared to 62 and 38% for CAGV. Postoperative IOP was significantly lower at 1-month and final follow-up (p = 0.02) as was the number of glaucoma medications at 3, 6, 12-months and final follow-up (p < 0.05) in the OAGV group. CONCLUSIONS: Ologen-augmentation increased the success and survival rates of AGVs in childhood glaucomas. Further, Ologen mitigated the hypertensive phase and decreased medication dependency. Longer follow-up with a greater number of eyes is required to fully evaluate the effectiveness of OAGV.
Subject(s)
Glaucoma Drainage Implants , Glaucoma , Child , Child, Preschool , Collagen , Follow-Up Studies , Glaucoma/surgery , Glycosaminoglycans , Humans , Infant , Intraocular Pressure , Retrospective Studies , Treatment Outcome , Visual AcuityABSTRACT
BACKGROUND: The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS. METHODS: Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1 year. The number of eyes with glaucoma (IOP ≥ 21 mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20 mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis. RESULTS: In 32 patients identified with ARS (median age at presentation 6.9 years, 0-58.7 years; median follow-up 5.4 years, 1.1-43.7 years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3 years (0-57.9 years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8 ± 9.3 mmHg (median 20 mmHg, 4-45 mmHg) on 1.0 ± 1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2 ± 1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3 ± 3.9 years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8 ± 12.7 years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5 ± 13.5 years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7 ± 1.9 years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9 ± 2.3 years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7 ± 3.5 years of IOP control. At final follow-up, mean IOP (12.6 ± 3.8 mmHg, median 11.8 mmHg, 7-19 mmHg) in glaucomatous eyes was significantly decreased (p < 0.0001), but there was no difference in number of glaucoma medications (1.6 ± 1.5, p = 0.1). CONCLUSIONS: In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.
Subject(s)
Anterior Eye Segment/abnormalities , Eye Abnormalities/complications , Eye Diseases, Hereditary/complications , Glaucoma/surgery , Adolescent , Adult , Anterior Eye Segment/physiopathology , Child , Child, Preschool , Cryosurgery , Eye Abnormalities/diagnosis , Eye Abnormalities/physiopathology , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/physiopathology , Female , Follow-Up Studies , Glaucoma/etiology , Glaucoma/physiopathology , Glaucoma Drainage Implants , Humans , Infant , Infant, Newborn , Intraocular Pressure/physiology , Male , Middle Aged , Retrospective Studies , Tonometry, Ocular , Trabeculectomy , Visual AcuityABSTRACT
Retinoic acid (RA), the active derivative of vitamin A (retinol), is an essential morphogen signaling molecule and major regulator of embryonic development. The dysregulation of RA levels during embryogenesis has been associated with numerous congenital anomalies, including craniofacial, auditory, and ocular defects. These anomalies result from disruptions in the cranial neural crest, a vertebrate-specific transient population of stem cells that contribute to the formation of diverse cell lineages and embryonic structures during development. In this review, we summarize our current knowledge of the RA-mediated regulation of cranial neural crest induction at the edge of the neural tube and the migration of these cells into the craniofacial region. Further, we discuss the role of RA in the regulation of cranial neural crest cells found within the frontonasal process, periocular mesenchyme, and pharyngeal arches, which eventually form the bones and connective tissues of the head and neck and contribute to structures in the anterior segment of the eye. We then review our understanding of the mechanisms underlying congenital craniofacial and ocular diseases caused by either the genetic or toxic disruption of RA signaling. Finally, we discuss the role of RA in maintaining neural crest-derived structures in postembryonic tissues and the implications of these studies in creating new treatments for degenerative craniofacial and ocular diseases.
Subject(s)
Craniofacial Abnormalities/etiology , Eye Abnormalities/etiology , Neural Crest/metabolism , Tretinoin/metabolism , Animals , Embryonic Induction , Humans , Neural Crest/embryology , Signal TransductionABSTRACT
Neural crest cells (NCCs) are vertebrate-specific transient, multipotent, migratory stem cells that play a crucial role in many aspects of embryonic development. These cells emerge from the dorsal neural tube and subsequently migrate to different regions of the body, contributing to the formation of diverse cell lineages and structures, including much of the peripheral nervous system, craniofacial skeleton, smooth muscle, skin pigmentation, and multiple ocular and periocular structures. Indeed, abnormalities in neural crest development cause craniofacial defects and ocular anomalies, such as Axenfeld-Rieger syndrome and primary congenital glaucoma. Thus, understanding the molecular regulation of neural crest development is important to enhance our knowledge of the basis for congenital eye diseases, reflecting the contributions of these progenitors to multiple cell lineages. Particularly, understanding the underpinnings of neural crest formation will help to discern the complexities of eye development, as these NCCs are involved in every aspect of this process. In this review, we summarize the role of ocular NCCs in eye development, particularly focusing on congenital eye diseases associated with anterior segment defects and the interplay between three prominent molecules, PITX2, CYP1B1, and retinoic acid, which act in concert to specify a population of neural crest-derived mesenchymal progenitors for migration and differentiation, to give rise to distinct anterior segment tissues. We also describe recent findings implicating this stem cell population in ocular coloboma formation, and introduce recent evidence suggesting the involvement of NCCs in optic fissure closure and vascular development.
Subject(s)
Eye/growth & development , Neural Crest/cytology , Organogenesis/physiology , Animals , HumansABSTRACT
Craniofacial and ocular morphogenesis require proper regulation of cranial neural crest migration, proliferation, survival and differentiation. Although alterations in maternal thyroid hormone (TH) are associated with congenital craniofacial anomalies, the role of TH on the neural crest has not been previously described. Using zebrafish, we demonstrate that pharmacologic and genetic alterations in TH signaling disrupt cranial neural crest migration, proliferation, and survival, leading to craniofacial, extraocular muscle, and ocular developmental abnormalities. In the rostral cranial neural crest that gives rise to the periocular mesenchyme and the frontonasal process, retinoic acid (RA) rescued migratory defects induced by decreased TH signaling. In the caudal cranial neural crest, TH and RA had reciprocal effects on anterior and posterior pharyngeal arch development. The interactions between TH and RA signaling were partially mediated by the retinoid X receptor. We conclude that TH regulates both rostral and caudal cranial neural crest. Further, coordinated interactions of TH and RA are required for proper craniofacial and ocular development.
Subject(s)
Face/embryology , Neural Crest/drug effects , Neural Crest/embryology , Skull/embryology , Thyroid Hormones/pharmacology , Tretinoin/pharmacology , Zebrafish/embryology , Animals , Antithyroid Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/metabolism , Eye/drug effects , Eye/embryology , Gene Expression Regulation, Developmental/drug effects , Gene Knockdown Techniques , Models, Biological , Muscle Development/drug effects , Neural Crest/cytology , Neural Crest/metabolism , Receptors, Thyroid Hormone/metabolism , Signal Transduction/drug effects , Skull/drug effects , Zebrafish Proteins/metabolismABSTRACT
PURPOSE: To identify specific factors and outcomes associated with corneal edema and Haabs striae in primary congenital glaucoma (PCG). METHODS: The medical records of patients with PCG from 2011 to 2023 with >3 months' follow-up were reviewed retrospectively. Preoperative details and final outcomes were compared between eyes with and without corneal findings. The right eye of bilateral cases and the affected eye in unilateral cases were included. RESULTS: A total of 58 patients (104 eyes, 69% male) underwent initial angle surgery at an average age of 297 ± 368 (median, 134) days. Corneal edema and Haabs striae were present preoperatively in 72 (69%) eyes of 41 patients and 68 (65%) eyes of 39 patients, respectively. Patients with corneal edema presented at a younger age (P < 0.0001) and with shorter axial length (P = 0.01) than those without edema. Univariate analysis showed that corneal edema was associated with worse visual acuity at final follow-up (OR = 4.4; 95% CI, 1.2-25.3). Patients with Haabs striae were older than those without striae (P = 0.04). After angle surgery, corneal edema was present at 1 month in 71% (95% CI, 52-84), at 2 months in 26% (95% CI, 12-42), at 3 months in 16% (95% CI, 6-30), and at 1 year in 3% (95% CI, 0-13). Corneal opacification did not resolve in 4 eyes of 3 patients after >4 years of follow-up. CONCLUSIONS: In our study cohort, corneal edema resolved in the majority of PCG cases within 2-3 months of initial angle surgery but was associated with younger age at presentation and worse visual acuity at final follow-up.
Subject(s)
Corneal Edema , Glaucoma , Humans , Male , Female , Corneal Edema/etiology , Corneal Edema/complications , Intraocular Pressure , Retrospective Studies , Cornea , Glaucoma/surgery , Follow-Up StudiesABSTRACT
The MAF gene encodes a transcription factor in which pathogenic variants have been associated with both isolated and syndromic congenital cataracts. We aim to review the MAF variants in the C-terminal DNA-binding domain associated with non-syndromic congenital cataracts and describe a patient with a novel, disease-causing de novo missense variant. Published reports of C-terminal MAF variants and their associated congenital cataracts and ophthalmic findings were reviewed. The patient we present and his biological parents had genetic testing via a targeted gene panel followed by trio-based whole exome sequencing. A 4-year-old patient with a history of bilateral nuclear and cortical cataracts was found to have a novel, likely pathogenic de novo variant in MAF, NM_005360.5:c.922A>G (p.Lys308Glu). No syndromic findings or anterior segment abnormalities were identified. We report the novel missense variant, c.922A>G (p.Lys308Glu), in the C-terminal DNA-binding domain of MAF classified as likely pathogenic and associated with non-syndromic bilateral congenital cataracts.
Subject(s)
Cataract , Mutation, Missense , Proto-Oncogene Proteins c-maf , Humans , Cataract/genetics , Cataract/congenital , Cataract/pathology , Proto-Oncogene Proteins c-maf/genetics , Male , Child, Preschool , Protein Domains , Exome SequencingABSTRACT
Axenfeld-Rieger syndrome (ARS) is a rare congenital disease that is primarily characterized by ocular anterior segment anomalies but is also associated with craniofacial, dental, cardiac, and neurologic abnormalities. Over half of cases are linked with autosomal dominant mutations in either FOXC1 or PITX2, which reflects the molecular role of these genes in regulating neural crest cell contributions to the eye, face, and heart. Within the eye, ARS is classically defined as the combination of posterior embryotoxon with iris bridging strands (Axenfeld anomaly) and iris hypoplasia causing corectopia and pseudopolycoria (Rieger anomaly). Glaucoma due to iridogoniodysgenesis is the main source of morbidity and is typically diagnosed during infancy or childhood in over half of affected individuals. Angle bypass surgery, such as glaucoma drainage devices and trabeculectomies, is often needed to obtain intraocular pressure control. A multi-disciplinary approach including glaucoma specialists and pediatric ophthalmologists produces optimal outcomes as vision is dependent on many factors including glaucoma, refractive error, amblyopia and strabismus. Further, since ophthalmologists often make the diagnosis, it is important to refer patients with ARS to other specialists including dentistry, cardiology, and neurology.
ABSTRACT
BACKGROUND: The main contact lens for pediatric aphakia has historically been a silicone elastomer lens (Silsoft SuperPlus). Due to supply chain disruption, many aphakic children required an alternative lens. We performed quantitative and qualitative comparisons between Silsoft SuperPlus and alternative aphakic soft contacts. METHOD: Sixty-nine aphakic eyes of 49 patients wearing Silsoft SuperPlus lenses underwent the refitting process into an alternative soft contact. Data collected included lens parameters, visual acuity, keratometry, horizontal visible iris diameter, and over-refraction. A 6-question survey assessing the patients'/guardians' experience with Silsoft SuperPlus versus the alternative lens was conducted at initial fit and 1-3 months post-fit. RESULTS: Twenty-four patients (49 %), 4(8 %), and 1(2 %) were refit into Flexlens Definitive 74, Biofinity XR, and Intelliwave Pro Toric lenses, respectively. Sixteen patients (34 %) remained in Silsoft SuperPlus due to personal lens surplus or inability to handle the new lens while 2(4 %) opted for glasses. Silsoft SuperPlus was typically successful in eyes with average keratometry (AveK) 7.4-7.6 mm. Flexlens Definitive 74 required a base curve 0.4 mm steeper than the AveK. Patients'/guardias' reported a trend toward greater comfort with handling Silsoft SuperPlus, however, patients experienced less adverse side effects with the alternative soft contact lenses. CONCLUSIONS: Flexlens Definitive 74 was an adequate alternative to Silsoft SuperPlus in aphakic children, however lens parameters must be steepened. Keratometry streamlined the contact lens fitting process. Alternative soft lenses are a cost-effective alternative to Silsoft contact lenses.
Subject(s)
Aphakia, Postcataract , Contact Lenses, Hydrophilic , Lens, Crystalline , Humans , Child , Aphakia, Postcataract/therapy , Contact Lenses, Hydrophilic/adverse effects , Visual Acuity , Silicone ElastomersABSTRACT
PURPOSE: To analyze corneal biomechanics, specular microscopy, and optical coherence tomography-angiography findings in children with glaucoma. METHODS: Pediatric patients (<18 years of age) with glaucoma (n = 38), increased cup:disk ratio and normal intraocular pressure (IOP) glaucoma suspects (n = 36), and controls (n = 67) were prospectively enrolled. Patients underwent testing with Ocular Response Analyzer, CellChek Specular Microscope, and Heidelberg OCT-A. RESULTS: Average age of participants was 12.4 ± 3.5 years, with no difference between groups (P = 0.71). Glaucoma patients had undergone more intraocular surgeries (P < 0.0001) and showed worse logMAR visual acuity (P < 0.0001) than suspects or controls. Central corneal thickness (CCT) was greater in glaucoma patients (642.8 ± 85.9 µm [P < 0.0001]) and suspects (588 ± 43.7 µm [P = 0.003]) compared with controls (561 ± 39.9 µm). Corneal hysteresis (CH) was decreased in eyes with glaucoma (10.4 ± 3.0) compared with controls (11.7 ± 1.5 [P = 0.006]), but not suspects (11.3 ± 2.0 [P = 0.1]). Glaucoma patients had lower endothelial cell density (2028.4 ± 862.7 [P < 0.0001]) and greater average cell area (547.2 ± 332.4 [P < 0.0005]) compared with suspects (2919.3 ± 319.1, 347.5 ± 46.2) and controls (2913.7 ± 399.2, 350.8 ± 57.7), but there was no difference in polymegathism (P = 0.12) or pleomorphism (P = 0.85). No differences in vessel density or vessel skeletal density in the retinal vascular complex (P = 0.3077, P = 0.6471) or choroidal vascular complex (P = 0.3816, P = 0.7306) were detected. CONCLUSIONS: Children with glaucoma showed thicker corneas with lower endothelial cell density and greater cell area, but no difference in retinal/choroidal vascular densities compared with suspects and controls.
Subject(s)
Glaucoma, Open-Angle , Glaucoma , Ocular Hypertension , Humans , Child , Adolescent , Intraocular Pressure , Tomography, Optical Coherence , Glaucoma/diagnosis , Cornea , AngiographyABSTRACT
Stickler Syndrome is typically characterized by ophthalmic manifestations including vitreous degeneration and axial lengthening that predispose to retinal detachment. Systemic findings consist of micrognathia, cleft palate, sensorineural hearing loss, and joint abnormalities. COL2A1 mutations are the most common, however, there is a lack of genotype-phenotype correlations. Retrospective, single-center case series of a three-generation family. Clinical features, surgical requirements, systemic manifestations, and genetic evaluations were collected. Eight individuals clinically displayed Stickler Syndrome, seven of whom had genetic confirmation, and two different COL2A1 mutations (c.3641delC and c.3853G>T) were identified. Both mutations affect exon 51, but display distinct phenotypes. The c.3641delC frameshift mutation resulted in high myopia and associated vitreous and retinal findings. Individuals with the c.3853G>T missense mutation exhibited joint abnormalities, but mild ocular manifestations. One individual in the third generation was biallelic heterozygous for both COL2A1 mutations and showed ocular and joint findings in addition to autism and severe developmental delay. These COL2A1 mutations exhibited distinct eye vs. joint manifestations. The molecular basis for these phenotypic differences remains unknown and demonstrates the need for deep phenotyping in patients with Stickler syndrome to correlate COL2A1 gene function and expression with ocular and systemic findings.
Subject(s)
Eye Diseases, Hereditary , Hearing Loss, Sensorineural , Retinal Detachment , Humans , Retinal Detachment/genetics , Retrospective Studies , Collagen Type II/genetics , DNA Mutational Analysis , Hearing Loss, Sensorineural/genetics , Eye Diseases, Hereditary/genetics , MutationABSTRACT
PURPOSE: To compare outcomes of bilateral lateral rectus recession (BLRc) paired with either bilateral inferior oblique myectomy (BIOm) or bilateral inferior oblique recession (BIOc) to correct V-pattern exotropia. METHODS: The medical records of children (≤18 years) who underwent BLRc with BIOm or BIOc (10 mm) for V-pattern intermittent exotropia between December 2020 and May 2022 and who had at least 6 months' postoperative follow-up were reviewed. Outcomes included horizontal alignment, bilateral inferior oblique action, stereopsis, postoperative exotropia control score, and additional strabismus surgeries. Analysis was stratified by preoperative V pattern into subgroups of 10Δ-14Δ and ≥15Δ. RESULTS: Fifty patients underwent BLRc with BIOm (n = 26) or BIOc (n = 24), with no difference in age, sex, or follow-up length. Preoperatively, there were no differences in stereopsis, horizontal or vertical deviations in primary position, strabismus control, or inferior oblique overaction (IOOA). The BIOc group had greater preoperative V pattern than the BIOm group (18.1 ± 6.8 D vs 14.3 ± 7.0 D, resp. [P = 0.03]). There was no difference in BLRc surgical dose. At final follow-up (mean, 448 ± 189 days), both groups showed a postoperative decrease in horizontal deviation, amount of V pattern, and IOOA. For patients with ≥15Δ V pattern, BIOm decreased V pattern amount at distance (P = 0.02) and IOOA (P = 0.0035) more than BIOc, and BIOm patients had better control of residual strabismus at distance (P = 0.03) compared with the BIOc group overall, as well as for both V pattern subgroups. Two patients with BIOm and one with BIOc underwent additional strabismus surgery. CONCLUSIONS: BIOm or BIOc in combination with BLRc decreased the angle of exotropia and improved control. However, BIOm, especially with large V patterns, had a greater effect on decreasing the V pattern and IOOA and showed better control of residual strabismus.
Subject(s)
Exotropia , Ocular Motility Disorders , Orbital Diseases , Strabismus , Child , Humans , Exotropia/surgery , Eye Movements , Ophthalmologic Surgical Procedures , Vision, Binocular , Retrospective Studies , Oculomotor Muscles/surgery , Ocular Motility Disorders/surgery , Strabismus/surgery , Orbital Diseases/surgery , Treatment OutcomeABSTRACT
BACKGROUND: Terson syndrome is the phenomenon of intraocular hemorrhage in the setting of subarachnoid hemorrhage (SAH). Vision loss can lead to morbidity for the affected individual. Aneurysmal SAH related to intracranial aneurysms is rare in children. Studies have shown the incidence of Terson syndrome in adults with aneurysmal SAH to be over 40%; however, few cases of Terson syndrome in pediatric aneurysmal SAH have been reported. OBSERVATIONS: A 9-year-old male presented with altered mental status and seizures. Computed tomographic angiography showed aneurysmal SAH from a ruptured, left-sided posterior inferior cerebellar artery aneurysm. The patient underwent endovascular treatment with coiling and external ventricular drainage for SAH. Ophthalmological consultation for blurry vision revealed the diagnosis of Terson syndrome with decreased vision in the left eye, which was managed conservatively. LESSONS: Terson syndrome after SAH can occur in children. Prompt ophthalmological evaluation in pediatric patients with aneurysmal SAH is vital for recognition and management to decrease overall morbidity.
ABSTRACT
Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye. Mutations in the transcription factors FOXC1 or PITX2 are the most well-studied genetic manifestations of this syndrome. Due to the rarity this syndrome, ARS-associated neurological manifestations have not been well characterized. The purpose of this systematic review is to characterize and describe ARS neurologic manifestations that affect the cerebral vasculature and their early and late sequelae. PRISMA guidelines were followed; studies meeting inclusion criteria were analyzed for study design, evidence level, number of patients, patient age, whether the patients were related, genotype, ocular findings, and nervous system findings, specifically neurostructural and neurovascular manifestations. 63 studies met inclusion criteria, 60 (95%) were case studies or case series. The FOXC1 gene was most commonly found, followed by COL4A1, then PITX2. The most commonly described structural neurological findings were white matter abnormalities in 26 (41.3%) of studies, followed by Dandy-Walker Complex 12 (19%), and agenesis of the corpus callosum 11 (17%). Neurovascular findings were examined in 6 (9%) of studies, identifying stroke, cerebral small vessel disease (CSVD), tortuosity/dolichoectasia of arteries, among others, with no mention of moyamoya. This is the first systematic review investigating the genetic, neurological, and neurovascular associations with ARS. Structural neurological manifestations were common, yet often benign, perhaps limiting the utility of MRI screening. Neurovascular abnormalities, specifically stroke and CSVD, were identified in this population. Stroke risk was present in the presence and absence of cardiac comorbidities. These findings suggest a relationship between ARS and neurovascular findings; however, larger scale studies are necessary inform therapeutic decisions.