There is clinical and genetic heterogeneity in this syndrome and precise classification of many families remains elusive without knowing the genotype. Mutations in at least four genes are responsible and all are are responsible for phenotypes transmitted in autosomal dominant patterns. Type 1 discussed here is caused by a mutation in the homeobox transcription factor gene, PITX2, located at 4q25-q26. A type of iris hypoplasia (IH)/iridogoniodysgenesis (IGDS) (IRID2; 137600) disorder has been classified separately but is caused by a mutation in PITX2 as well and many cases have the same systemic features. Mutations in the same gene have also been found in ring dermoid of the cornea (180550) and in some cases of Peters anomaly (604229).
RIEG2 (601499) is rare but a deletion of 13q14 has been reported in several cases. Mapping in a large family with 11 affected individuals yielded a locus in the same region. Clinical signs overlap types 1 and 3 with dental, craniofacial, and ocular features, but with hearing impairment and rare umbilical anomalies.
Mutations in the FOXC1 gene (6p25) may be responsible for RIEG3 (602482). However, a family has been reported with a severe 'Axenfeld-Rieger phenotype' in which a digenic etiology may have been responsible: patients had mutations in both FOXC1 and PITX2.
Heterozygous mutations in the PRDM5 gene (4q25-q26) have been identified in 4 members of a Pakistani family with typical features of the Axenfeld-Rieger syndrome. It is labeled type 4 Axenfeld-Rieger syndrome in this database.
