Primary congenital and developmental glaucomas

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. Although most glaucoma patients are elderly, congenital glaucoma and glaucomas of childhood are also important causes of visual disability. Primary congenital glaucoma (PCG) is isolated, non-syndromic glaucoma that occurs in the first three years of life and is a major cause of childhood blindness. Other early-onset glaucomas may arise secondary to developmental abnormalities, such as glaucomas that occur with aniridia or as part of Axenfeld-Rieger syndrome. Congenital and childhood glaucomas have strong genetic bases and disease-causing mutations have been discovered in several genes. Mutations in three genes (CYP1B1, LTBP2, TEK) have been reported in PCG patients. Axenfeld-Rieger syndrome is caused by mutations in PITX2 or FOXC1 and aniridia is caused by PAX6 mutations. This review discusses the roles of these genes in primary congenital glaucoma and glaucomas of childhood.

Figure 1.

Clinical features of Axenfeld-Rieger Syndrome in a patient with a PITX2 mutation. DNA sequencing of the PITX2 gene in a female with Axenfeld-Rieger syndrome identified a novel heterozygous mutation of a canonical splicing sequence within intron 3, IVS3-1delG. This patient had classic features of Axenfeld-Rieger syndrome including bilateral iris hypoplasia (panel A and B); posterior embryotoxon (panel A and B indicated with black arrows); polycoria (panel A and B indicated with white arrowheads); and corectopia (panel B indicated with an asterisk). This patient also had hypodontia and microdontia (panel C).

Figure 2.

Clinical features of aniridia in a patient with a PAX6 mutation. Whole genome DNA sequencing of the PAX6 gene in a female with aniridia and secondary glaucoma detected a tandem inversion (hg19:g.[chr11:31763505-40323405inv;chr11:40323414-43536635inv];[=]) on chromosome 11p13 (panel A) including the PAX6 gene. This inversion moved PAX6 away from a vital enhancer (DRR) (105) that is normally downstream of the PAX6 gene (top, wild-type configuration) to an inactive position millions of base pairs away (bottom, mutant configuration). This patient had an absence of visible iris tissue in both eyes (panel B, right eye; panel C, left eye). The edges of the natural lenses (indicated with black arrows) were visible due to the absence of visible iris tissue. There is bilateral cataract indicated by black arrowheads. Finally, the white arrowheads indicate Ahmed drainage valves that were surgically implanted to control intraocular pressure. This patient has severe secondary glaucoma with a near total cupping of the right optic nerve head (panel D) and a large optic cup with a thin rim of neural tissue remaining on the left optic nerve head (panel E). A normal optic nerve head is shown in panel F for comparison.