Goniodysgenesis and glaucoma: A perspective worth revisiting

Congenital maldevelopment of the iridocorneal angle, also known as goniodysgenesis, may occur as an isolated defect or in association with other ocular or generalized malformations. Histopathologically, its main features consist of a wide-open angle with a persistent endothelial covering,[1,2] a persistent uveal meshwork,[3] and a compact corneoscleral trabeculum,[4] with or without a hypoplasia of the canal of Schlemm.[5] The concept that congenital and juvenile glaucoma have a single basic pathology, namely gonidysgenesis, was proposed way back in 1939.[1,6] However, dysgenesis of the angle was found to be common even among eyes with high-pressure primary open-angle glaucoma.[7,8] The concept of correlating clinical manifestations with gonioscopic features among developmental glaucomas was also put forth by Gorin.[9] He observed a more severe clinical course of the disease in those with more severe gonioscopic anomaly. Ikui and Fukuda[10] suggested that the age of onset of primary glaucomas depended on the extent of immaturity of the angle tissues. Jerndal proposed that goniodysgenesis was hereditary, and that in contrast to the full-blown expression of goniodysgenesis in congenital glaucoma, reduced expression may lead to a long delay of the elevated IOP and glaucomatous optic neuropathy within the same family.[7] Since the biological principle of certain congenital malformations causing the late appearance of clinical manifestations is well known from other organs (e.g., polycystic kidney disease), it is not surprising that goniodysgenesis can also have an early or late manifestation. Goniodysgenesis may not always be apparent on enface gonioscopy. The signs of goniodysgenesis may be subtle and thus not easily detected or even looked for in patients with primary open-angle glaucoma (POAG). Tawara and Inomata observed the presence of thick compact tissue in the TM samples of juvenile glaucoma patients, irrespective of whether they had an apparent goniodysgenesis on gonioscopy.[11] Hence, what appears to be the morphologically normal angle on gonioscopy may harbor dysgenesis of the trabecular meshwork (TM) or even the Schlemm’s canal (SC). This has been our observation also, using high-definition ASOCT. We have shown that goniodysgensis can be picked up only on high-definition ASOCT, in cases when the angle appears apparently open and normal.[12,13] What is goniodysgensis? The line between what is normal and what is angle dysgenesis especially on gonioscopy or even ASOCT remains unclear. In our earlier work on juvenile open-angle glaucomas, we have defined what could be morphologic features of different types of goniodysgensis.[14] Grossly, it appears as a high iris insertion, prominent iris processes, or a featureless angle that gives the appearance of a membrane covering the TM. We have also attempted to define these on ASOCT.[12] On ASOCT, one can see the hyper-reflectivity in the region of the TM or uveal extension from the iris covering the TM or the absence of a discernible SC. However, the extent or severity of these features that would lead to a rise of IOP is still unknown. This is a much-needed area of research for glaucoma specialists. While so much information exists on the association of smoking, caffeine intake, glycemic, and cholesterol levels with POAG, there is nothing with regards to angle dysgenesis which forms the basis of raised IOP in POAG. The idea of goniodysgenesis among adult-onset POAG was floated 70 years ago and hopefully will resurface again given the large armamentarium of minimally invasive angle surgeries. Since goniodysgenesis is hereditary and so is POAG, it is obvious that it has a genetic basis. As of now, the most commonly associated gene for juvenile and adult-onset POAG is Myocilin (MYOC). Jerndal[7] showed autosomal dominant families of juvenile glaucoma with hereditary goniodysgenesis. The pedigrees described by him could be those with MYOC glaucoma. Whether MYOC mutations induce a goniodysgenesis is subject to debate currently. However, there is a report about a juvenile glaucoma family with a MYOC mutation having an evident goniodysgenesis.[15] We have also shown on high-definition ASOCT the presence of subtle TM dysgenesis even among MYOC glaucomas.[10] Of course more genes and their association with the increased resistance to outflow need to be discovered to explain other cases of early-onset or even late-onset POAG. Goniodysgenesis is also important in that it explains the risk of an eye-developing secondary glaucoma. There are many instances of patients on systemic steroids developing glaucoma in only one eye. Probably, the eyes with greater dysgenesis have the potential to be more susceptible to the effect of steroids compared to the contralateral eyes. Similarly, primary congenital glaucoma caused by CYP1B1 mutations may also present unilaterally. While both eyes may harbor goniodysgenesis, the affected eyes have been shown to have a more severe form of angle dysgenesis, while there are alternate pathways for aqueous outflow in the contralateral eyes, which seem to be anatomically protective toward the development of glaucoma.[16] Is goniodysgenesis more common in certain ethnic groups? MYOC-associated glaucoma is estimated to account for 2–4% of adult-onset POAG. Certain MYOC variants, like E352K, are found predominantly in individuals of African descent.[17] Notably, individuals of African descent are ~2.8x higher risk for glaucoma than other ethnic groups,[18] but no data to date implicates this variant in the disease. This also stems from our inability to have found genes with high biological impact, related to POAG. One needs to look at this from the perspective of differences in the prevalence of dysgenesis in certain ethnicities where early-onset POAG is more common. This should be an interesting topic for future research. From a therapeutic point of view also, it is important to identify angle dysgenesis. We have shown that eyes with goniodysgenesis are less likely to respond to angle-based procedures for lowering IOP like selective laser trabeculoplasty.[19,20] A question then arises: Could the genotype of the patient determine the type of angle surgery or minimally invasive glaucoma device insertion? It is not far that identification of the dysgenesis of the outflow channels will become important in determining which angle procedure will work. As we approach toward this reality, it is important to understand and teach the identification of angle dysgenesis, at least of the little we know of it. So possibly in the future, high-resolution ASOCT examinations of the angle would become more useful for POAG than for PACG.