Perspective
Axenfeld-Rieger syndrome in the age of molecular genetics

https://doi.org/10.1016/S0002-9394(00)00525-0Get rights and content

Abstract

%PURPOSE: To review the molecular genetics of Axenfeld-Rieger syndrome and related phenotypes and to discuss how this information might affect the way that we classify these disorders.

METHODS: A review of historical and recent literature on Axenfeld-Rieger syndrome and related disorders. The review includes clinical and molecular genetic literature relevant to these phenotypes.

RESULTS: Three chromosomal loci have recently been demonstrated to link to Axenfeld-Rieger syndrome and related phenotypes. These loci are on chromosomes 4q25, 6p25, and 13q14. The genes at chromosomes 4q25 and 6p25 have been identified as PITX2 and FKHL7, respectively. Mutations in these genes can cause a wide variety of phenotypes that share features with Axenfeld-Rieger syndrome. Axenfeld anomaly, Rieger anomaly, Rieger syndrome, iridogoniodysgenesis anomaly, iridogoniodysgenesis syndrome, iris hypoplasia, and familial glaucoma iridogoniodysplasia all have sufficient genotypic and phenotypic overlap that they should be considered one condition.

CONCLUSIONS: Axenfeld-Rieger syndrome is a term that can be used to describe a variety of overlapping phenotypes. To date, at least three known genetic loci can cause these disorders. The single most important feature of these phenotypes is that they confer a 50% or greater risk of developing glaucoma. Currently there is a fairly arbitrary grouping of disorders into small categories. Considering all of these phenotypes under the heading of Axenfeld-Rieger syndrome will allow easier communication between clinicians and scientists and eliminate arbitrary and confusing subclassification.

Section snippets

Chromosome 4q25 (gene = paired-like homeodomain transcription factor 2; PITX2) (MIM 601542)

Rieger syndrome has been reported in patients with a variety of chromosomal translocations and deletions. The most common site of chromosomal abnormality has been the long arm of chromosome 4 (4q).10 Murray and associates10 studied three small families with autosomal dominant Rieger syndrome (with ocular and systemic features). They performed linkage analysis in the interval on chromosome 4q where translocations were most common and found evidence of genetic linkage to this interval.

Axenfeld-rieger syndrome (MIM 180500)

: Posterior embryotoxon is a term used to describe a prominent and anteriorly displaced Schwalbe line. The posterior embryotoxon is visible at the slit lamp and is easily seen on gonioscopy. Some degree of posterior embryotoxon has been described in up to 15% of the population.25 However, the posterior embryotoxon that is commonly found in the normal population is typically subtle, while that seen in Axenfeld-Rieger syndrome can be dramatic. Although posterior embryotoxon is found in most

Discussion

This article has attempted to summarize what is known about the anterior segment dysgenesis disorders that make up Axenfeld-Rieger syndrome and related phenotypes. While these disorders can be split into small groups because of minor differences, it seems more logical to combine them under the umbrella of Axenfeld-Rieger syndrome. In a thorough review of Axenfeld-Rieger syndrome in 1983, Shields stated, “The overlapping of ocular and nonocular defects in these patients prevented

Acknowledgements

I am grateful to Jeffrey C. Murray, MD, Darryl Y. Nishimura, PhD, Elena Semina, PhD, Val C. Sheffield, MD, PhD, Edwin M. Stone, MD, PhD, and Ruth E. Swiderski, PhD, for allowing me to be a part of the exciting studies on molecular genetics that are taking place in their laboratories. I am also in debt to my good friend Hansjoerg E. Kolder, MD, PhD, for his careful translation of the original German literature.

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    This study was supported in part by grants RO1EY10564 and RO1EY12384 from the National Institutes of Health, Bethesda, Maryland; The Glaucoma Research Foundation, San Francisco, California; and an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York.

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