Patient Information

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Progressive iris dissolution in 10 year old over 4 years
Progressive iris dissolution in 10 year old over 4 years
Advanced iris dissolution and limbal opacification in an adult
Advanced iris dissolution and limbal opacification in an adult
Hypodontia and diastema
Hypodontia and diastema
Iris stroma dissolution in an adult with Rieger syndrome
Iris stroma dissolution in an adult with Rieger syndrome
Incomplete involution of umbilicus
Incomplete involution of umbilicus
Posterior embryotoxon
Posterior embryotoxon as part of anterior chamber dysgenesis (Courtesy of EyeRounds.org)

Axenfeld-Rieger Syndrome, Type 1

Clinical Characteristics

Ocular Features

Axenfeld-Rieger syndrome consists of a heterogeneous group of disorders with overlapping features.  Type 1 is described here. Common to all three 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

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 three 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

Treatment Options

The presence of glaucoma requires prompt and vigorous treatment but control is difficult with blindness too often the result.  Oral surgery may be beneficial for dental problems.  Low vision aids can be useful.

References

Weisschuh N. Digenic inheritance in axenfeld rieger syndrome. Hum Mutat. 2011 Oct;32(10):iv. doi: 10.1002/humu.21593.

PubMed ID: 
21932364

Law SK, Sami M, Piri N, Coleman AL, Caprioli J. Asymmetric phenotype of Axenfeld-Rieger anomaly and aniridia associated with a novel PITX2 mutation. Mol Vis. 2011;17:1231-8.

PubMed ID: 
21617748

Tümer Z, Bach-Holm D. Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. Eur J Hum Genet. 2009 Dec;17(12):1527-39.

PubMed ID: 
19513095

Sowden JC. Molecular and developmental mechanisms of anterior segment
dysgenesis.
Eye (Lond). 2007 Oct;21(10):1310-8. Review.

PubMed ID: 
17914434

Strungaru MH, Dinu I, Walter MA. Genotype-phenotype correlations in Axenfeld-Rieger malformation and glaucoma patients with FOXC1 and PITX2 mutations. Invest Ophthalmol Vis Sci. 2007 Jan;48(1):228-37.

PubMed ID: 
17197537

Alward WL. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J
Ophthalmol. 2000 Jul;130(1):107-15. Review.

PubMed ID: 
11004268

Jorgenson RJ, Levin LS, Cross HE, Yoder F, Kelly TE. The Rieger syndrome. Am J Med Genet. 1978;2(3):307-18.

PubMed ID: 
263445