Anterior megalophthalmos (AM) is a non-progressive, bilateral congenital enlargement of the anterior segment, first described by Seefeld in 1914 (1). It is characterized by megalocornea (horizontal diameter ≥12.5 mm) with a very deep anterior chamber and enlarged ciliary ring, although corneal histology and thickness remain normal or moderately thin (2). The main causes of decreased vision in patients with AM are premature cataracts at the age of 30–50 years and lens subluxation (3). Posterior segment abnormalities, such as vitreous fibrillar degeneration with liquefaction and retinal detachment, are also found in patients with AM (4). AM is also known as X-linked megalocornea since X-linked recessive inheritance exists in 50% of patients with AM (5). The AM locus maps on the long arm of the X chromosome in the region Xq12-q26 (6). Autosomal transmission is the cause of AM in 40% of the patients, and de novo mutations at this locus were found in the remaining 10% of patients (7). CHRDL1 gene is determined as a virulence gene of AM while Marfan syndrome, Trisomy 21, Apert syndrome, and mucolipidosis type II were found to be associated with AM (8).

Although several challenging cases of cataract surgeries in patients with AM have been reported (3, 9–14), no study has focused on the biometric and structural ocular manifestations of patients with AM with a control group, as AM is a rare and sporadic disease.

To better define the biometric and structural ocular manifestations of patients with AM, we analyzed the ocular findings in 15 patients with AM and compared them to those of the control group.

Anterior megalophthalmos is a hereditary disease that affects the anterior segment of the eye. The enlarged cornea of AM may be mistaken for congenital glaucoma; however, IOP and corneal clarity are normal in patients with AM (15). However, a review showed that only 3 out of 57 patients (5.26%) presented with glaucoma (2). AM can also be easily confused with megalocornea that has no other ocular abnormalities, excluding corneal enlargement. There is a need to distinguish AM from other developmental abnormalities characterized by corneal enlargement by biometric and structural ocular manifestations.

In simple megalocornea, there are no other ocular abnormalities, excluding corneal enlargement. In patients with AM, the cornea is enlarged, typically with increased ACD. Meire and Delleman (5) reported that axial length was increased in patients with AM, which was also found in our study with a median axial length of 26.04 ± 3.25 mm. Corneal endothelial cells have a normal morphology and cell density, which suggests that corneal endothelial cell hyperplasia occurs concurrently with excessive corneal growth.

Some special pathological changes in patients with AM have been reported in this study, including iris atrophy (36.67%), posterior iris bowing (66.67%), and enlarged ciliary ring (53.33%). AM is a non-progressive condition as lens dislocation (73.33%) and premature development of lens opacities (36.67%) were the most intriguing features of AM observed in this study. Further eye growth with age is not progressively abnormal. With the development of early cataract and lens subluxation, this could be considered a progression of the constellation of features, but AL remains stable after entering adulthood. Additionally, there are several challenges in cataract surgery for patients with AM caused by deep anterior chambers, zonular anomalies, and large capsular bags (7). Many intraoperative and postoperative complications have been reported, such as vitreous loss, lens subluxation/luxation, retinal detachment, and IOL dislocation (16).

Intraocular lens instability related to an oversized capsular bag and zonular anomalies is the highest concern for ophthalmologists. Implantation of IOLs in lens capsule bags or in the ciliary sulcus is only appropriate in cases without significant zonular weakness. In reviewing the literature on AM, different approaches have been applied to avoid IOL decentration (9). Sharan and Billson (11) prescribed aphakic and aphakic contact lenses to patients for visual rehabilitation. Implantation of large custom-made IOLs to ensure endocapsular fixation in problematic capsular bags was reported by Vaz and Osher (17). However, due to high expenses, custom-made IOLs are difficult to obtain. Custom-made IOLs handle the problem of oversized capsular bags while still having a high risk of being dislocated due to 360° zonular weakness caused by an enlarged ciliary ring (13, 16).

To manage insufficient capsular support, iris-claw IOLs have started to be noticed in patients with AM. Retro-pupillary iris-claw IOLs have been proposed as excellent alternatives for patients with AM (18). Compared with sutured anterior chamber IOLs, retropupillary iris-claw IOLs enclavated to the iris are supposed to reduce the potential for complications associated with anterior chamber IOLs, such as corneal endothelial damage, anterior synechia, and glaucoma (10). In recent research, anterior chamber and PC iris-claw IOL fixation were equally effective and safe in eyes with inadequate capsular support (11). Retropupillary iris-claw IOLs also have some disadvantages. The enlarged incision may result in unpredictable astigmatism after surgery. Meanwhile, iridoleptynsis is a common symptom observed in patients with AM, although the additional development of iris lesions may occur after suturing the iris claw (11).

In this study, we tested the agreement of optical biometers in measuring the ACD and WTW in the eyes of patients with AM, as we found a large gap among the different biometers. After comparing the ACD measured by three optical biometers in patients with AM, the results showed that ACD measured by Pentacam HR was significantly lower than that measured by IOLMaster 700 and UBM. A significant difference was also found between the Pentacam HR and IOL Master 700 in WTW. WTW measured by the IOL Master 700 was obviously higher than that measured by the Pentacam HR, indicating that Pentacam HR and IOL Master 700 could not be used interchangeably for measuring WTW. Both devices used anterior segment photography to obtain WTW measurements. The accuracy of WTW measurement depends on algorithms for limbus edge detection and on the light source of the device, as well as the quality of the image captured by optical biometers. It is noted that the WTW value is required in the diagnosis of AM and is also required for choices of IOL implantation methods, including IOL implantation in the ciliary sulcus, in capsular bags, and in trans-sclera suture fixation. Therefore, to ensure safety, the maximum value of WTW was used to diagnose AM. Since the calculated power can vary depending on WTW and ACD measurements, it should be carefully considered before cataract surgery for patients with AM.

X-linked recessive inheritance is the most common form of AM, which was found in 50% of AM cases, while the autosomal transmission was observed in 40% of patients with AM, and sporadic transmission was observed in the remaining 10% (19). Gene linkage studies have suggested that the AM locus maps in the region Xq12-q26.9, and men account for 90% of AM cases (8). However, in our series of 15 patients with AM, there were 7 women and 8 men. Homozygous mutations in CPAMD8 in 3 of 5 AM unrelated patients were identified by whole-exome sequencing (Table 5). As a candidate gene for cataract development, CPAMD8 was mapped to chromosome 19p13.2–p13.3, spanning approximately 130 kb. Wiggs (20) identified mutations in CPAMD8 associated with anterior segment dysgenesis. Affected patients showed similar features, including a bilateral enlarged corneal diameter, ectopia lentis, and premature cataract, which matched the patients with AM (21).

This study has several limitations. First, as AM is a rare disease, only 15 patients with AM (30 eyes) were collected for a period of 5 years (January 2016 to January 2021) with 14,000 cataract surgeries per year in the study hospital. Only three unrelated female patients underwent whole-exome sequencing. Larger studies of patients with AM may be necessary in the future. Second, because the IOLMaster 700 was used from March 2018 to January 2021, some ocular characteristics measured by IOLMaster 700 were not documented before March 2018; therefore, we excluded patients with missing data when assessing agreement of the IOLMaster 700 and Pentacam HR in patients with AM. Third, a longitudinal study is needed to record postoperative complications and visual acuity in patients with AM.

Corneal biometric manifestations of patients with AM included flatter cornea, lower total corneal astigmatism, and longer axial length, although corneal morphology and thickness remained normal or moderately thin. Posterior iris bowing, lens subluxation, and very deep anterior chambers are the most characteristic findings in AM. The ACD and WTW values measured by the Pentacam HR were significantly lower than those measured by the IOLMaster 700. Thus, we suggest that various examinations should be carefully considered before determining an AM diagnosis.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The Institutional Review Board approved the study with the extension of our randomized controlled trial (ChiCTR2000039132). All the patients were signed the standard consent form including consent for data privacy.

YJ and T-HC were responsible for the research design of the article. MZ and J-HC helped to collect the data of followed MFS patients. T-HC and Z-XC was responsible for statistical analyses. All authors reviewed and revised the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, JH declared a shared affiliation with the authors to the handling editor at the time of the review.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.