OMIM ID:
Axenfeld-Rieger Syndrome, Type 1
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Axenfeld-Rieger syndrome consists of a heterogeneous group of disorders with overlapping features. Common to all types are the presence of ocular, dental, facial, skeletal abnormalities and autosomal dominant inheritance. Anterior chamber dysgenesis of some form is universally present and severe glaucoma occurs in 50% of patients. This may have its onset in childhood with typical symptoms of congenital glaucoma such as photophobia, excessive tearing and corneal clouding. Hypoplasia of the iris is common and when progressive may result in an ectopic pupil and/or pseudopolycoria. Iris insertion and Schwalbe’s line are often anteriorly displaced with iridocorneal adhesions, a pattern that leads to the inclusion of this disorder among those with iridogoniodysgenesis or anterior chamber dysgenesis. Pupillary ectropion of the posterior pigmented layer of the iris may be seen.
There is considerable clinical overlap among conditions with iris dysgenesis. Some patients with typical systemic features of Axenfeld-Rieger syndrome may even have typical anterior chamber features of Axenfeld-Rieger anomaly in one eye and severe iris hypoplasia resembling aniridia in the other.
Systemic Features
Dental anomalies and mid-facial hypoplasia secondary to underdeveloped maxillary sinuses are among the most common systemic features in type 1. The nasal root often appears abnormally broad and the lower lip appears to protrude. The teeth are frequently small and conical in shape with wide spaces between them (diastema). Some teeth may be missing. The umbilicus may fail to involute normally and retains excessive, redundant skin that sometimes leads to the erroneous diagnosis of an umbilical hernia for which unnecessary surgery may be performed. Hypospadius is frequently present while cardiac defects, sensorineural deafness, and anal stenosis are less common.
Genetics
Inheritance
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.
Pedigree
Autosomal dominant
Autosomal dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission