Dr. Giacomo Bacci (Ophthalmology, A.O.U. Meyer, Florence, Italy), in his presentation titled “The COL4A1/COL4A2 Ocular Phenotypic Spectrum: The Pediatric Ophthalmology Perspective,” described the ocular manifestations associated with COL4A1 and COL4A2 mutations, followed by a study on carrier patients.

The COL4A1 and COL4A2 genes produce type IV collagen, a crucial protein for the structure and function of various tissues, including the eye. Collagen plays a significant role in the anterior part of the eye, being present in structures such as the lens capsule, the inner limiting membrane of the retina, hyaloid vessels, and Bruch’s membrane. The expression of COL4A1 and COL4A2 genes in these ocular structures is particularly high, explaining why mutations in these genes often manifest with ocular symptoms. Dr. Bacci and his team found that the trabecular meshwork, lens capsule, optic nerve, and blood vessels are areas with markedly high collagen expression, justifying the frequent ocular manifestations in patients with these mutations.

The genotype-phenotype correlations for these conditions can seem vague because collagen manifestations in the eye are varied and affect different structures. Among the most common clinical signs reported in the literature, one of the most notable is retinal arterial tortuosity. However, it is often not immediately recognizable unless one is aware of a pathology related to COL4A1 and COL4A2 genes. Other more evident signs include congenital cataracts, glaucoma, microphthalmia, microcornea, and anterior segment dysgenesis. One of the most frequent anterior segment dysgeneses is the Axenfeld-Rieger spectrum, characterized by a malformation that can mimic anisocoria macroscopically. Advanced technologies like optical coherence tomography (OCT) allow for detailed observation of the iridocorneal angle anatomy and identification of dysgeneses that might otherwise go unnoticed.

Dr. Bacci and his team also conducted a study on a series of patients carrying COL4A1 and COL4A2 mutations, using diagnostic tools such as anterior segment microscopy and fundus camera for the eye’s posterior segment, along with OCT. This enabled them to perform advanced phenotyping and identify subclinical manifestations that would otherwise be difficult to detect. For instance, they observed small posterior lens opacities in some patients that did not affect vision but were visible with OCT.

Thanks to these technologies, it was possible to perform particularly advanced phenotyping of the iridocorneal angle, allowing detailed observation of its anatomy and angle study, thus obtaining highly refined anatomical details. Furthermore, in the posterior segment of the eye, OCT allows, through image processing software, the estimation of major neuro-ophthalmological structures. Among these are the ganglion cell complex and the inner plexiform layer, which are fundamental for the formation of optic nerve fibres that transmit signals from the eye to the brain. The evaluation of the peripapillary nerve fibre layer, which constitutes the optic nerve, is today correlated with many neuro-ophthalmological pathologies. The eye is a small window into neurodegenerative diseases.

In carriers of COL4A1 and COL4A2 mutations, these alterations can be detected with infrared imaging showing vascular tortuosity, as described in the literature. However, careful attention is required, as these forms often do not create visible functional deficits, and patients see well, presenting only this subtle anatomical characteristic. For example, in a 7-year-old girl, a unilateral iridocorneal angle anomaly was observed, which would have gone unnoticed if not sought, despite the girl being otherwise healthy. Knowing she is a carrier of COL4A1 or COL4A2 mutations allows identifying this as anterior segment dysgenesis that needs attention.

Therefore, performing accurate phenotyping of asymptomatic carriers has allowed us to see that while there were no functional problems, there were still issues present. Retinal vascular tortuosity, for instance, is not a constant finding but rather sporadic. However, other findings were perfectly in line with those reported in the literature. Dr. Bacci and his team found visual defects such as anterior segment anomalies, strabismus, and even a choroidal nevus, all conditions that did not create significant problems on their own but were useful for understanding the manifestations of COL4A1 and COL4A2 mutations in affected family members with a complete phenotype.

Results from 13 carriers (11 with COL4A1 mutations and 2 with COL4A2 mutations) showed three cases of cataract, two patients with minimal signs of anterior segment dysgenesis, retinal vascular tortuosity, and various other anomalies. These findings confirm that ocular manifestations are frequent and that thorough analysis is essential for accurate diagnosis. Taken in isolation, these manifestations may seem of little clinical importance, but combined, they provide a significant picture that underscores the importance of carrier screening. This screening can reveal subclinical manifestations that, if properly monitored, can prevent complications such as glaucoma.

Dr. Bacci concluded his presentation by highlighting the need to increase awareness of the ocular manifestations of COL4A1 and COL4A2 mutations among ophthalmologists to ensure adequate and timely monitoring.