A novel homeobox mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome associated with brain, ocular, and dental phenotypes.

Axenfeld-Rieger Syndrome (ARS) is a genetically heterogeneous birth defect characterized by malformation of the anterior segment of the eye associated with glaucoma. Mutation of the PITX2 homeobox gene has been identified as a cause of ARS. We report a novel Arg5Trp missense mutation in the PITX2 homeodomain, which is associated with brain abnormalities. One patient had a small sella turcica likely to reflect hypoplasia of the pituitary gland and consistent with the critical role identified for Pitx2 in pituitary development in mice. Two patients had an enlarged cisterna magna, one with a malformed cerebellum, and two had executive skills deficits one in isolation and one in association with a below average intellectual capacity. The mutation caused a typical ARS ocular phenotype. All affected had iris hypoplasia, anterior iris to corneal adhesions, and corectopia. The ocular phenotype varied significantly in severity and showed some asymmetry. All affected also had redundant peri-umbilical skin, a hypoplastic maxilla, microdontia, and hypodontia missing between 20 and 27 teeth with an unusual pattern of tooth loss. Dental phenotypes were documented as they are often poorly characterized in ARS patients. All affected individuals showed an absence of first permanent molars with variable absence of other rarely absent teeth: the permanent upper central incisors, maxillary and mandibular first and second molars, and the mandibular canines. Based on the distinctive dental anomalies, we suggest that the dental phenotype can assist in predicting the presence of a PITX2 mutation and the possibility of brain abnormalities.