Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

Abstract

Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder, which encompasses a range of congential malformations affecting the anterior segment of the eye. ARS shows genetic heterogeneity and mutations of the two genes, PITX2 and FOXC1, are known to be associated with the pathogenesis. There are several excellent reviews dealing with the complexity of the phenotype and genotype of ARS. In this study, we will attempt to give a brief review of the clinical features and the relevant diagnostic approaches, together with a detailed review of published PITX2 and FOXC1 mutations.

Figure 1

Ocular changes observed in Axenfeld–Rieger syndrome. (a) Corectopia on the right eye (displaced pupil is shown by an arrow); (b) Polycoria (the extra hole on the iris is shown by an arrow); (c) Posterior embryotoxon, the prominent Schwalbe's line is indicated with arrows; (d) Iris strands bridging the chamber angle as seen on gonioscopy.

Figure 2

(a) Clinical photographs of father (33 years) and son (3 years) affected with Axenfeld–Rieger syndrome. ( b) Female patient (two and half years). All the patients show similar morphological features, including telecanthus, broad nasal bridges and prominent lower lips. The father and the female patient have maxillary hypoplasia and additionally the female patient has dental anomalies with small crowns.

Figure 3

Diagnostic strategy for ARS. A mutation involving PITX2 or FOXC1 can be found in about 40%, leaving the diagnosis in 60% of the patients to rest on clinical features only. Mutation screening of exons 5 and 6 of PITX2; and the first 550 bp of FOXC1 is recommended initially as these regions code for the DNA-binding domains of the respective genes and they are the hot spots for mutations.