The morphology of angle dysgenesis assessed by ultrasound biomicroscopy and its relationship with glaucoma severity and mutant genes in Axenfeld-Rieger syndrome

Introduction

Axenfeld-Rieger syndrome (ARS) is characterized by developmental abnormalities involving multiple systems and organs, mainly affecting ocular anterior segment (1). It originates from abnormal migration of neural crest cells, causing the developmental defects of iridocorneal angle and aqueous humor outflow structures (2,3). Patients are at 50% risk of developing glaucoma, which can result in optic nerve damage and irreversible loss of the visual field (4,5). ARS is genetically heterogeneous, and 40–63% of patients have genetic defects in 2 developmental transcription factor genes: FOXC1 (the forkhead box C1 gene) or PITX2 (the pituitary homeobox 2 gene) (6-11).

Previous reports have described the anomalous anterior segment of ARS, which may include posterior embryotoxon, iridocorneal adhesions, iris hypoplasia, incomplete angle recession, trabecular meshwork atrophy, and Schlemm’s canal occlusion (1,5,12,13). However, due to the opacity of the cornea or young age of some patients, it is often difficult to clearly observe the chamber angle structure by means of slit lamp or gonioscopy.

Ultrasound biomicroscopy (UBM) is an ultrasound technique which provides noninvasive and dynamic high-resolution imaging of the anterior ocular segment in vivo (14). It is particularly important for patients with opaque cornea (15) and useful in visualizing the structures behind the iris (16,17). Thus far, a few studies have depicted the characteristics of anterior segment structure in ARS using UBM (10,18-20); however, no report has evaluated and classified the iridocorneal angle morphology of ARS in detail. Our study therefore aimed to assess the morphology of chamber angle in ARS and to determine the correlation of anterior chamber angle morphology with glaucoma severity and mutant genes. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-23-348/rc).

Methods

Patients

We consecutively recruited 42 patients diagnosed with ARS and glaucoma simultaneously between April 2000 and December 2021 in Eye, Ear, Nose, and Throat Hospital of Fudan University. Our cohort was a mixture of familial and isolated cases of ARS, including 4 familial cases and 38 isolated cases. Patients were followed up for a median duration of 79 (IQR, 38–128) months. This study was approved by the Institutional Review Board of Eye, Ear, Nose, and Throat Hospital of Fudan University (No. KJ2011-04) and followed the tenets of the Declaration of Helsinki (as revised in 2013). Written consent forms were obtained from all patients or their legal guardians. The criteria for inclusion were as follows: (I) congenital ocular abnormalities, including malformations of the anterior chamber angle, posterior embryotoxon, iridocorneal adhesions traversing the anterior chamber, iris hypoplasia, polycoria, and corectopia; and (II) with or without systemic abnormalities, including craniofacial abnormalities, dental anomalies, redundant periumbilical skin, and other systemic manifestations (21,22). Eyes with prior histories of trauma, surgeries, or uveitis were excluded. Diagnosis of glaucoma in adults was based on at least 2 of the following clinical features: intraocular pressure (IOP) >21 mmHg, glaucomatous optic disc damage (cup to disc ratio of >0.5 or inter-eye asymmetry of >0.2, neuroretinal rim thinning, notching, disc hemorrhage, etc.), or glaucomatous visual field defects (4). According to Childhood Glaucoma Research Network criteria, childhood glaucoma was diagnosed if at least 2 of the following features were present: (I) IOP >21 mmHg; (II) glaucomatous optic neuropathy (progressively increased cup to disc ratio; cup to disc ratio asymmetry of ≥0.2 in similar-sized optic discs; and thinning of the focal rim); (III) progressive myopia or myopic shift with increased ocular dimensions exceeding normal growth; (IV) reproducible visual field defect with no other possible causes; (V) or corneal findings including Haab’s striae, corneal edema, corneal diameter >11 mm in a neonate, >12 mm in a child under 1 year old, or >13 mm at any age (23).

Clinical investigation

Of all participants, detailed medical histories were collected, including ocular and systemic medication, family history, history of trauma, and surgeries. Comprehensive ophthalmologic examinations were conducted, including visual acuity examination, ophthalmoscopy, slit-lamp biomicroscopy, gonioscopy, IOP measurement using Goldmann applanation tonometer or Tono-Pen (Reichert Technologies, Depew, NY, USA), anterior segment photography, color fundus photography, B-mode ultrasonography, and A-mode ultrasonography. Adults and cooperative children underwent visual field examinations with the Octopus 101 (Haag-Streit, Inc., Köniz, Switzerland) or Humphrey Visual Field Analyzer 750 (Zeiss-Humphrey Systems, Dublin, CA, USA).

The following information was recorded and analyzed for each eye: onset age of glaucoma, untreated IOP, vertical cup to disc ratio (VCDR), corneal clarity, age at surgery, type of surgery, and the surgical outcome. Corneal clarity was scored as follows: 1, corneal transparence; 2, mild corneal opacity with visible iris; 3, severe corneal opacity with invisible iris; and 4, severe corneal opacity with neovascularization. An addition of 0.5 was included if there were Haab’s striae (24). Surgical failure was defined as a postoperative IOP >21 mmHg with the necessity of additional antiglaucoma medications or secondary surgical therapy.

UBM examination

UBM (MD-300L; MEDA Co., Tianjin, China) with a 50-MHz resolution was performed for all the patients before surgeries. The UBM examinations were conducted by experienced technicians in Eye, Ear, Nose, and Throat Hospital of Fudan University following the same operating procedure. Patients were placed in the supine position, and a water bath in contact with the eye was applied to examine the anterior segment. Patients older than 10 years old underwent UBM examination under topical anesthesia, while those younger than 10 years old underwent general anesthesia. The morphology of the iridocorneal angle was classified into 6 types: type A, pure high insertion of the iris root with or without abnormal tissue membrane covering the anterior chamber angle (Figure 1A); type B, posterior embryotoxon, shown as hyperechoic foci on the posterior corneal surface, essentially indicating a prominent and anteriorly displaced Schwalbe’s line (Figure 1B); type C, iris process, indicated as abnormal strands of the peripheral iris extending toward the protruding Schwalbe’s line (Figure 1C); type D, trabecular-iris synechia corresponding to the anterior synechia of the iris root on the trabecular meshwork without anterior chamber angle recess (Figure 1D); type E, peripheral iridocorneal adhesion involving anterior displacement of the iris and iridocorneal adhesion (Figure 1E); type F, goniodysgenesis, characterized by loss of normal chamber angle configuration with indistinguishable scleral spur and deep posterior chamber (Figure 1F). The anterior chamber angle was scanned for the inferior, temporal, superior, and nasal quadrants. Two scans in each quadrant per eye were conducted and each scan was recorded as a 0.5 quadrant for analysis. The UBM images were evaluated by 2 investigators who were blinded to the clinical details and genetic testing results. Eyes exhibiting prominence of a specific type of the iridocorneal angle morphology were categorized into the corresponding groups. The ciliary body on UBM images was also evaluated. Ciliary body hypoplasia was defined as a short and thin ciliary body with unclear anatomical characteristics.

Figure 1 Morphology of the iridocorneal angle was classified into 6 types. (A) Type A, pure high insertion of the iris root with or without abnormal tissue membrane covering the anterior chamber angle. (B) Type B, posterior embryotoxon, shown as hyperechoic foci (white arrow) on the posterior corneal surface. (C) Type C, iris process, indicated as abnormal strands of peripheral iris extending to the protruding Schwalbe’s line. (D) Type D, trabecular-iris synechia corresponding to the anterior synechia of the iris root onto the trabecular meshwork without anterior chamber angle recess. (E) Type E, peripheral iridocorneal adhesion involving anterior displacement of the iris and iridocorneal adhesion. (F) Type F, goniodysgenesis, characterized by the loss of a normal chamber angle configuration with indistinguishable scleral spur and a deep posterior chamber.

Genetics analysis

Candidate genes were sequenced in all patients with next-generation sequencing using the Illumina Miseq platform (Illumina, San Diego, CA, USA) with the 2×300 bp paired-end read module. The panel covered 289 genes associated with anterior segment dysgenesis and glaucoma. The average coverage depth was 100 times, and 90% of targeted bases were covered 40 times or more. All detected variants and the segregation on all available family members were verified through Sanger sequencing.

Statistical analysis

All data were analyzed using SPSS version 20.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism software version 9.0 (GraphPad Software, San Diego, CA, USA). Onset age of glaucoma and age at surgery with nonnormal distributions were evaluated using the Kruskal-Wallis test with Dunn post hoc test. Comparisons of sex, surgical rate, type of surgery, surgical failure rate, and anterior chamber angle type among patients with different mutant genes were assessed using Pearson chi-squared test or Fisher exact test with Bonferroni post hoc test. To adjust for the correlation between 2 eyes of patients with both eyes included in the analysis, generalized estimating equations were used to compare the onset age of glaucoma, untreated IOP, VCDR, corneal clarity score, and age at surgery. A generalized linear mixed model was employed to compare the surgical rate, type of surgery, surgical failure rate, and proportion of the ciliary body hypoplasia among the 6 groups of eyes. Statistical significance was set at P<0.05.

Results

Demographic characteristics

In total, 42 patients were enrolled in this study. Among them, 26 were male (61.9%) and 16 were female (38.1%). Of the 42 patients with glaucoma, 39 cases were bilateral and 3 cases were unilateral. The onset age of glaucoma ranged from 0 to 70 years, with 10 patients (10/42, 23.8%) and 19 eyes (19/81, 23.5%) developing glaucoma in infancy (0–1 year), 16 patients (16/42, 38.1%) and 30 eyes (30/81, 37.0%) in adolescence (1–18 years), 11 patients (11/42, 26.2%) and 22 eyes (22/81, 27.2%) in young adulthood (18–40 years), and 5 patients (5/42, 11.9%) and 10 eyes (10/81, 12.3%) after middle age (>40 years). In all patients with both eyes diagnosed with glaucoma, the interval of occurrence of glaucoma between the 2 eyes was less than 1 year.

Clinical characteristics

The UBM images of all 42 participants were obtained. Of the 84 eyes, 3 were excluded for poor quality images and another 3 were excluded for lack of glaucoma development. In all of the remaining 78 eyes, different degrees of iris atrophy with high insertion of the iris root were present. Ciliary body hypoplasia was observed in 45 eyes (45/78, 57.7%). The iridocorneal angle morphology of each patient is shown in Table S1. Moreover, 57 eyes (57/78, 73.1%) had at least 2 types of angle morphology, whereas 21 eyes (21/78, 26.9%) had an identical type of anterior chamber angle in the 4 quadrants. By number of quadrants, type B (89.5/312, 28.7%) was the most common type, while type D was the rarest one (18/312, 5.8%).

The 78 eyes with UBM examinations in our study were categorized as type A group (n=14), type B group (n=22), type C group (n=9), type D group (n=5), type E group (n=20), and type F group (n=8) according to their dominant types of anterior chamber angle (>2 quadrants of the angle). Both eyes were categorized into the same group in all patients with bilateral UBM images. The clinical characteristics and comparison analysis among the 6 groups are shown in Table 1. There were statistically significant differences in onset age of glaucoma (P<0.001) and age at surgery (P<0.001) between the groups. Eyes in type C and D groups developed glaucoma and underwent surgery at an earlier age, with the median being less than 1 year of age; eyes in the type B, E, and F groups developed glaucoma and underwent surgery at a relatively later age, with medians of 10 to 25 years of age; eyes in the type A group developed glaucoma and underwent surgery at a later age, with the median being more than 30 years of age. Eyes in type A group had the lowest untreated IOP, with a median of 24.4 mmHg, while the other groups all had medians greater than 30.0 mmHg (P=0.016). The VCDR was significantly larger in type D and F groups than in the other groups (P=0.001). Furthermore, the type A group had the lowest surgical rate (28.6%) compared to the others (from 70% to 100%), with a marginal P value (P=0.086). The corneal clarity scores and surgical failure rate within 5 years were not statistically significantly different among the 6 groups. We also compared the proportions of the ciliary body hypoplasia among different groups of eyes and found that eyes in the type F group had the highest proportion (8/8, 100.0%), eyes in the type A group (10/14, 71.4%) and type E group (13/20, 65.0%) had a relatively higher proportion, eyes in the type B group (10/22, 45.5%) and type D group (2/5, 40.0%) had a relatively lower proportion, and eyes in type C group had the lowest proportion (2/9, 22.2%). These differences were statistically significant (P=0.017).

Genetic defect and dysgenesis of the iridocorneal angle

A total of 15 patients were detected as carrying FOXC1 defects, 14 patients were detected as carrying PITX2 defects, and 13 patients showed no defects in any candidate genes (Table S1). All detected variants were heterozygous and predicted to be pathogenic (8). As shown in Table 2, there was no statistically significant difference in sex (P=0.870) among the patients with FOXC1 defects, patients with PITX2 defects, and patients without defects in the 2 genes. The patients with FOXC1 defects were more likely to have an earlier onset age of glaucoma than were patients with PITX2 defects (P=0.007) and those without defects in the 2 genes (P=0.001). There was no significant difference in untreated IOP (P=0.878) or VCDR (P=0.926) among the 3 groups. With respect to the corneal clarity, patients with FOXC1 defects had higher scores than did patients with PITX2 defects (P=0.036) and those without defects in the 2 genes (P=0.002). Although no significant difference was found in the surgical rate (P=0.826), the patients with FOXC1 defects underwent surgery at a statistically significantly younger age than did patients with PITX2 defects (P=0.002) and those without defects in the 2 genes (P=0.004). No statistically significant difference in onset age of glaucoma, corneal clarity, or age at surgery was observed between patients with PITX2 defects and those without defects in the 2 genes. During the follow-up, we found that the patients with FOXC1 defects had a lower rate of surgical failure within 5 years than did patients with PITX2 defects (P=0.020).

With regard to the anterior chamber angle dysgenesis, patients with FOXC1 defects had angle type B, type C, and type D more frequently compared to patients with PITX2 defects, whereas patients with PITX2 defects had angle type A, type E, and type F more frequently compared to patients with FOXC1 defects. Comparison of angle dysgenesis types of the different mutant genes is presented in Table 3 and Figure 2.

Figure 2 Pie chart of the morphological angle type for patients with different mutant genes. Each pie chart corresponds to a group of patients and depicts the frequency distribution of 6 types of anterior chamber angle: Type A, pure high iris insertion; Type B, posterior embryotoxon; Type C, iris process; Type D, trabecular-iris synechia; Type E, peripheral iridocorneal adhesion; and Type F, goniodysgenesis.

Discussion

UBM is a valuable and reliable technique, which provides high-resolution images similar to a microscope (25). It contributes to the evaluation of anterior segment structure, especially for those not easily accessible by conventional clinical examination underneath a turbid cornea (20,26). Moreover, compared with anterior segment optical coherence tomography, UBM can visualize and evaluate the structures of the ciliary body and therefore is the best tool for patients with anterior segment dysgenesis who often have iris anterior adhesions (16,17,27).

Based on the reported studies, the pathogenesis of ARS involves the developmental arrest of structures derived from neural crest cells in the third trimester of pregnancy resulting in the retention of endothelial layer on the iridocorneal angle and iris, together with the incomplete posterior sliding of uveal tissue (5). Contraction of the retained strands leads to the abnormalities of anterior chamber (5). Previous studies have described the angle features of ARS as the peripheral iris extending toward a prominently and centrally displaced Schwalbe’s line, with the thickness varying from thin to thick. The presence of an anterior iris root insertion, along with a rudimentary Schlemm’s canal, can impair the outflow of aqueous humor and consequently contribute to the onset or progression of glaucoma (28,29). In this study, we considered 6 types of iridocorneal angle morphology of ARS. High insertion of the peripheral iris was observed in all eyes, which has also been reported by others as being a potential risk factor for glaucoma (5,21). Other abnormalities, including prominent Schwalbe’s line in type B, iris process in type C, trabecular-iris synechia in type D, and peripheral iridocorneal adhesion in type E, although different in morphology, all originate from the deposition and contraction of the basement membrane by the primordial endothelial layer. Furthermore, UBM demonstrated ciliary body hypoplasia in 57.7% eyes, suggesting that the developmental defect in ARS involves not only the anterior chamber angle and iris but also the ciliary body. The type A angle morphology of ARS in our study shared similarities with the ultrasound biomicroscopic features reported in primary congenital glaucoma (PCG), which also arises from the hindered posterior sliding of uveal tissue. These shared features include a thin iris, small ciliary body, abnormal tissue membrane, anterior iris insertion, and absence of Schlemm’s canal (30,31), thus constituting evidence supporting the phenotypic overlap between ARS and PCG.

In this study, eyes in the type A group had a lower untreated IOP and surgical rate and developed glaucoma and underwent glaucoma surgery at a relatively later age than did the eyes in the type B, C, D, and E groups, indicating that the presence of posterior embryotoxon or iridocorneal adhesions may aggravate the development of glaucoma. Previous studies have demonstrated that the pathogenetic mechanism of glaucoma in ARS is the obstruction of aqueous outflow due to a rudimentary or absent Schlemm’s canal and the compact trabecular meshwork caused by developmental failure of the intertrabecular spaces (5,32). Thus, we speculate that a larger extent of the posterior embryotoxon and iridocorneal adhesions may be a sign of the poorer chamber angle development and, as a result, predispose eyes to a greater risk of development of glaucoma in ARS. Furthermore, we found that eyes in the type E group, despite having severe iridocorneal adhesions, developed glaucoma and underwent surgery at a later age than did those in the type C and D groups with mild iridocorneal adhesions. This suggests that the extent of iridocorneal adhesions did not correlate with the severity of glaucoma, which is consistent with previous studies (3). It seems that the severity of glaucoma may be correlated with the degree of health in the remaining unclosed angles. Furthermore, since the IOP balance was simultaneously influenced by the secretion and drainage of aqueous humor, this phenomenon might also be explained by the different degrees of hypoplasia of ciliary body in ARS, which was observed in more than half of our patients and was also highly common in other anterior segment dysgenesis diseases. Notably, we examined a special morphology of chamber angle maldevelopment (type F) in this study, which was characterized by the absence of observable angle structures under gonioscopy. We found that eyes having angle type F in all quadrants developed glaucoma in adolescence (16–22 years) instead of infancy, leaving the question of aqueous humor drainage pathway unclear.

In a previous study, we reported that patients with FOXC1 defects tended to be diagnosed with ARS at a younger age than did those with PITX2 defects (8). Here, we further compared other clinical characteristics between FOXC1-defect carriers and PITX2-defect carriers and found that FOXC1-defect carriers had poorer corneal transparency and developed glaucoma and underwent surgery at a significantly younger age than did PITX2-defect carriers. However, PITX2-defect carriers had a worse surgical prognosis than did FOXC1-defect carriers although this is consistent with a previous study (4). Since PITX2-defect carriers tended to have extensive iridocorneal adhesion and a relatively older age at onset, we performed glaucoma filtering surgery (trabeculectomy and drainage implant) on most patients (9/10, 90.0%) with the PITX2 defect. Meanwhile, we performed trabeculotomy on most patients (8/12, 66.7%) with the FOXC1 defect. Therefore, the difference of surgical failure rates between these 2 groups of patients was possibly associated with the difference in the type of surgery. In addition, we found there to be a certain correlation between the type of the iridocorneal angle morphology and the mutant genes. FOXC1-defect carriers tended to have posterior embryotoxon, iris process, and trabecular-iris synechia (type B, type C, and type D), whereas PITX2-defect carriers usually had pure high iris insertion, peripheral iridocorneal adhesion, and goniodysgenesis (type A, type E, and type F). This suggests that the developmental alterations leading to the chamber angle changes are not precisely the same between the 2 mutant genes, which may correlate with the difference in the function of the 2 genes and their involvement in eye development.

The majority of eyes with ARS require multiple surgeries to achieve long-term IOP control (33). In our study, we followed up the patients and observed a surgical success rate without additional antiglaucoma medication of 78.2% (43/55) at 5 years. Specifically, trabeculotomy showed a success rate of 93.8% (15/16), while filtering surgery exhibited a success rate of 71.8% (28/39). In another study, a series of 38 primary combined trabeculotomy-trabeculectomy procedures and 6 primary trabeculectomy procedures in ARS demonstrated a 93% complete success rate at up to 5 years (2). Furthermore, another study reported the following success rates for ARS: 48% at 5 years for goniotomy, 33% at 15 years for trabeculotomy or combined trabeculotomy and trabeculectomy, and 65% at 10 years for trabeculectomy with antifibrotics (33). The success rate of our study is thus comparable to those reported by other studies. The variations in outcomes across studies may be due to differences in surgical procedures, follow-up duration, and patient-related factors.

The limitations of our study include the sample size of each group being small, owing to the very low incidence of ARS. Our patients were recruited from glaucoma clinics, and most were diagnosed with glaucoma and ARS simultaneously. Therefore, we did not assess the angle features of ARS without glaucoma, and our findings may not apply to all patients with ARS. Finally, since the type of surgery was different among patients, the prognosis of ARS might have been affected.

Conclusions

ARS is a multisystemic developmental disorder, which primarily affects the eyes. Patients are at risk of developing glaucoma throughout their lives, and therefore long-term follow-up is necessary. Our findings provide a basis for classification system of anterior chamber angle dysgenesis in vivo and have significant implications for explaining the risk of glaucoma to patients with ARS following UBM examinations and genetic testing results.

Acknowledgments

The authors are grateful to the Biobank of the Eye, Ear, Nose, and Throat Hospital of Fudan University. The authors would like to thank Youbing Guo, Kailun Lv, Jinling Cao, Aibei Xu, and Bingbing Qu from Amplicon Gene (Shanghai, China) for the helpful bioinformatics analysis. The authors would also like to thank all of the patients and their families.

Funding: This work was supported by the National Natural Science Foundation of China (No. 81870692); the Shanghai Committee of Science and Technology, China (No. 20S31905800); the Clinical Research Plan of SHDC (No. SHDC2020CR6029); the National Key Research and Development Program of China (No. 2020YFA0112700); the State Key Program of National Natural Science Foundation of China (No. 82030027); and the Subject of Major projects of the National Natural Science Foundation of China (No. 81790641).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-23-348/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-348/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Eye, Ear, Nose, and Throat Hospital of Fudan University (No. KJ2011-04). Written consent forms were obtained from all patients or their legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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