Genetic and developmental basis of renal coloboma ( papillorenal ) syndrome

The clinical presentation of optic nerve anomalies associated with renal hypodysplasia should alert the clinician to the possibility that a patient may have renal coloboma syndrome, a condition also known as papillorenal syndrome (OMIM#120330). The optic nerve findings could be described as a ‘dysplasia’, characterized by absent central vessels with the emergence of vessels from the periphery of the optic nerve papilla. The optic nerve findings in this condition have been referred to as ‘coloboma’ and a fraction of affected patients have clinical evidence of optic fissure closure defects. Mutations in the gene PAX2 are currently the only known genetic basis for renal coloboma (papillorenal) syndrome and are found in half of patients. Animal models have been instructive in demonstrating that PAX2 is critical for optic fissure closure and vascular routing in the retina. The co-occurrence of optic nerve anomalies in patients who developed end stage renal disease was first recognized 30 years ago in two separate reports by Reiger et al. [1] and Karcher et al. [2]. Affected family members had optic nerve abnormalities described as ‘morning glory anomaly’ with deeply excavated optic nerves, abnormal passage of the optic vessels at the periphery of the disc rather than its center and a central glial tuft [1,2]. A total of 10 years later, Weaver et al. reported a case of two brothers, both with optic nerve colobomas, interstitial nephritis and renal failure [3]. Weaver noted the similarity of the optic nerve colobomas in his patients with the ‘morning glory anomaly’, previously reported by Karcher et al. [1]. Weaver and coauthors called this condition renal coloboma syndrome. The following year, Bron et al. reported a family with an autosomal dominant condition, whose affected members exhibited optic disc dysplasia, microphthalmia, morning glory anomaly, optic nerve glial remnants, central serous retinopathy and renal failure [4]. Bron et al. reviewed a number of conditions where eye and kidney findings predominated. These authors suggested the name papillorenal syndrome to describe a variety of conditions where optic nerve and kidney abnormalities are observed [4]. Sanyanusin et al. provided the first evidence that renal coloboma (papillorenal) syndrome was caused by autosomal dominant mutations in the transcription factor gene PAX2. In this report, a father and three children were described to have optic disc dysplasia/optic nerve coloboma and renal hypodysplasia [5,6]. Following this report, Sanyanusin et al. published a second article where they identified a PAX2 mutation in the previously Lisa A Schimmenti Department of Pediatrics and Ophthalmology, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 730, Minnesota, MN 55455, USA Tel.: +1 612 624 5613 Fax: +1 612 626 2993 [email protected] Renal coloboma syndrome, also known as papillorenal syndrome, is characterized by optic nerve anomalies and kidney hypodysplasia. Autosomal dominant mutations in the gene encoding the paired box transcription factor PAX2 can be identified in nearly half of all patients with this phenotype. The primary ophthalmologic findings include congenital central retinal vasculature absence associated with abnormalities in retinal blood vessel patterning and deeply excavated optic discs. Other published findings include optic nerve hypoplasia, optic nerve cyst, optic nerve pits, retinal coloboma, microphthalmia and scleral staphyloma. Visual acuity ranges from normal to severe impairment. Up to one third of affected patients will develop end-stage renal disease. Mouse and zebrafish with Pax2/pax2a mutations provide developmentally based explanations for the observed phenotypic observations in affected patients.