Ocular manifestations of CHARGE syndrome in a pediatric cohort with genotype/phenotype analysis.

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.

Concurrent adjacent strabismus surgery with glaucoma drainage device placement in childhood glaucomas.

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.

Evaluation of parameters for early detection of pediatric keratoconus.

BACKGROUND: Keratoconus in children is often more severe and rapidly progressive compared to adults. While Scheimpflug imaging (Pentacam) improves screening, there are no established pediatric guidelines. Due to challenges in diagnosis, we aimed to correlate clinical factors with abnormal imaging results to aid in the development of screening protocols. METHODS: A single-center retrospective cohort analysis of patients 3-18 years screened for keratoconus with ophthalmic examination and initial Scheimpflug imaging between 2021 to 2023. Scheimpflug indices including final D, ART max, and calculated CAIRO 8, which is a corneal metric combining pachymetry, ART max, and elevation, were compared to published pediatric ranges for normal and keratoconus corneas. RESULTS: Seventy-eight patients (11.8 ± 3.9 years) were screened with the majority referred due to high and/or progressive astigmatism (74 patients, 94%). Forty-nine patients (63%) were male and 48 (62%) self-reported Hispanic ethnicity. Average astigmatism was 4.9 ± 1.8 D and 86% had with-the-rule astigmatism. Fourteen patients (18%) had corneal findings on slit lamp. Average LogMAR CDVA was 0.243 ± 0.274 D. By Pentacam, 55 (70%) patients had ≥ 1 indeterminate or keratoconus value. Patients stratified as keratoconus by all parameters were older (15 vs. 11 years, p = 0.015-0.02), had worse visual acuity (p < 0.0001), and were more likely to have oblique astigmatism (0.0002-< 0.0001) and corneal abnormalities on examination (p < 0.00001) compared to eyes with normal or indeterminate indices. CONCLUSIONS: Older age, lower visual acuity, oblique astigmatism, and corneal findings were more commonly found in patients with abnormal screening Pentacam. Most patients clinically suspicious for keratoconus had ≥ 1 indeterminate/abnormal indices. Future studies will follow these patients to identify clinical risk factors for progression.

DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

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.

Ahmed to Baerveldt glaucoma drainage device exchange in pediatric patients.

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.

Otx2b mutant zebrafish have pituitary, eye and mandible defects that model mammalian disease.

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.

Clinical outcomes and visual prognostic factors in congenital aniridia.

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.

Ologen augmentation of Ahmed glaucoma drainage devices in pediatric glaucomas.

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.

Surgical outcomes of Glaucoma associated with Axenfeld-Rieger syndrome.

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.

What's retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development.

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.

Neural crest derivatives in ocular development: discerning the eye of the storm.

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.

Thyroid hormone and retinoic acid interact to regulate zebrafish craniofacial neural crest development.

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.

Visual and surgical outcomes of childhood glaucoma following cataract surgery.

PURPOSE: To evaluate frequency of surgery and post-treatment outcomes in glaucoma following cataract surgery (GFCS). METHODS: The medical records of patients with GFCS were reviewed retrospectively. Lensectomy and glaucoma surgery details and final examination findings were collected. Inclusion criteria included history of lensectomy at <1 year of age, diagnosis of glaucoma, and at least 1 year of follow-up. RESULTS: Of 169 eyes of 127 GFCS patients (66 male, 58 bilateral cases), 88 eyes (52%) of 73 (57%) patients underwent glaucoma surgery (median, 3.5 years of age at first glaucoma surgery; median of two glaucoma surgeries). At final follow-up (mean, 13.6 ± 7.0 years), eyes requiring glaucoma surgery had worse visual acuity (P = 0.01) and greater cup:disk ratio (P < 0.01). GFCS patients with history of bilateral congenital cataracts had better visual acuity in affected eyes than those with history of unilateral congenital cataract (P < 0.01). Angle surgery (n = 56), Baerveldt devices (n = 38), Ahmed valves (n = 19), and cycloablation (n = 21) showed 1-year survival rates between 64% and 75%. Baerveldt implants showed the highest 5- and 10-year survival rates, at 65% and 43%, respectively. CONCLUSIONS: More than 50% of eyes with GFCS in our study cohort required at least one glaucoma surgery. Glaucoma surgery and history of unilateral cataract were associated with worse visual acuity outcomes.

Factors and outcomes associated with corneal edema and Haabs striae in primary congenital glaucoma.

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.

Keratin 8/18a.1 Expression Influences Embryonic Neural Crest Cell Dynamics and Contributes to Postnatal Corneal Regeneration in Zebrafish.

A complete understanding of neural crest cell mechanodynamics during ocular development will provide insight into postnatal neural crest cell contributions to ophthalmic abnormalities in adult tissues and inform regenerative strategies toward injury repair. Herein, single-cell RNA sequencing in zebrafish during early eye development revealed keratin intermediate filament genes krt8 and krt18a.1 as additional factors expressed during anterior segment development. In situ hybridization and immunofluorescence microscopy confirmed krt8 and krt18a.1 expression in the early neural plate border and migrating cranial neural crest cells. Morpholino oligonucleotide (MO)-mediated knockdown of K8 and K18a.1 markedly disrupted the migration of neural crest cell subpopulations and decreased neural crest cell marker gene expression in the craniofacial region and eye at 48 h postfertilization (hpf), resulting in severe phenotypic defects reminiscent of neurocristopathies. Interestingly, the expression of K18a.1, but not K8, is regulated by retinoic acid (RA) during early-stage development. Further, both keratin proteins were detected during postnatal corneal regeneration in adult zebrafish. Altogether, we demonstrated that both K8 and K18a.1 contribute to the early development and postnatal repair of neural crest cell-derived ocular tissues.

A Case of Non-Syndromic Congenital Cataracts Caused by a Novel MAF Variant in the C-Terminal DNA-Binding Domain-Case Report and Literature Review.

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.

Ophthalmological Manifestations of Axenfeld-Rieger Syndrome: Current Perspectives.

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.

Corneal characteristics and OCT-angiography findings in pediatric glaucoma and glaucoma suspects.

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.

Characteristics of a Three-Generation Family with Stickler Syndrome Type I Carrying Two Different COL2A1 Mutations.

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.

Soft contact lens options in the management of pediatric aphakia - A quantitative and qualitative assessment.

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.