Axenfeld–Rieger spectrum (ARS) is a form of anterior segment dysgenesis characterized by posterior embryotoxon (prominent and anteriorly displaced Schwalbe’s line) and iridocorneal strands usually directly to the embryotoxon. Other findings may include iris malformations, corectopia, and/or polycoria (▶ Fig. 8.1). There is an approximately 50% lifetime risk for developing glaucoma at any age. Systemic findings may or may not be present. These include facial, dental (▶ Fig. 8.2), umbilical (▶ Fig. 8.3), and skeletal abnormalities. Previously, terms such as Axenfeld anomaly, Axenfeld syndrome, Rieger’s anomaly, and Rieger’s syndrome have been used to describe specific combinations of ocular and/or systemic findings. Molecular genetics has allowed the recognition of the wide spectrum of expression even with the same gene mutation and thus led to the use of the term ARS to include all patients. ARS is usually a bilateral, yet often asymmetric condition. Isolated posterior embryotoxon is not uncommon in the general population, perhaps as frequent as 15%.
Fig. 8.1 Axenfeld–Rieger spectrum. There is polycoria, and marked iris dysgenesis. Arrows indicate posterior embryotoxon.
Fig. 8.2 Tooth anomalies in a patient with Axenfeld–Rieger spectrum. Note microdontia, oligodontia, and abnormal tooth shape.
Fig. 8.3 Periumbilical redundant skin in a patient with Axenfeld–Rieger spectrum.
8.2 Molecular Genetics
ARS is genetically and phenotypically heterogeneous. Axenfeld–Rieger type 1 (RIEG1, OMIM 180500) is caused by PITX2 gene mutation, while Axenfeld–Rieger type 3 (RIEG3, OMIM 602482) is caused by FOXC1 gene mutation. Axenfeld–Rieger type 2 (RIEG2, OMIM 601449) is linked to chromosome 13q14, but the gene has not been identified. PITX2 (autosomal dominant, 4q25, OMIM 601542) and FOXC1 (autosomal dominant, 6p25, OMIM 601090) genes account for approximately 40% of ARS cases. Type 1 is reported to be associated with dental and umbilical disorders, while type 2 is associated with heart and hearing defects, or with isolated ocular defects. Other genes that when mutated have ocular and systemic abnormalities that include features of ARS are listed in ▶ Table 8.1.
Gene | Findings |
PAX6 | Ectropion uvea, corectopia, iris hypoplasia, cataract |
JAG1 | Alagille syndrome; posterior embryotoxon |
FOXC2 | Lymphedema-distichiasis syndrome; iris hypoplasia, corectopia |
CYP1B1 | ARS associated with protruding umbilicus and dental anomalies |
LAMB2 | Pierson syndrome; iris hypoplasia, ectropion uvea, posterior embryotoxon |
PRDM5 | Congenital glaucoma, ectopia pupil, iris hypoplasia, corneal opacity, posterior embryotoxon, posterior subcapsular cataract |
PIK3R1 | SHORT syndrome; ARS |
COL4A1 | Brain small vessel disease with or without ocular anomalies, including ARS |
Abbreviation: SHORT, Short stature, Hyperextensibility, Hernia, Ocular depression (enophthalmos), Rieger anomaly, and Teething delay. | |
8.3 Differential Diagnosis
8.3.1 Peters Anomaly (OMIM 604229)
Peters anomaly (OMIM 604229) is characterized by central corneal opacity with posterior corneal defect, and iridocorneal and/or lenticular corneal adhesions. Some patients may also express signs of ARS, in particular posterior embryotoxon.
8.3.2 Congenital Glaucoma (OMIM 231300)
Although glaucoma at birth or in infancy may be a feature of ARS, in congenital glaucoma there are no anatomic anomalies of the anterior segment as seen in ARS. In congenital glaucoma, there may be heterochromia, radialization of the iris stroma, and/or peripheral iris stromal atrophy. Gonioscopy reveals patches of high iris insertion over the trabecular meshwork but neither anteriorization of Schwalbe’s line nor iridocorneal adhesions.
8.3.3 Aniridia (OMIM 612469; 607108)
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