Renal hypoplasia without optic coloboma associated with PAX2 gene deletion.

PAX2 gene encodes a transcription factor that belongs to the paired-box family of homeotic genes and is widely expressed during the development of both ductal and mesenchymal components of the urogenital system. Human PAX2 gene maps on chromosome 10q24q25 and comprises 12 exons. Exons 1–4 encode the paired box domain, which is essential for DNAbinding activity. At early stages, the gene is expressed in neural tube cells. Later on, its expression is detected in the developing urogenital system as well as in the ear, eye and central nervous system (CNS). In the urogenital system, PAX2 is expressed in the induced nephrogenic mesenchyme, during the mesenchymal-toepithelial transition that preludes to glomerulus formation. Its expression is also detected in the branching ureteric bud, in collecting duct epithelia and in uterus, oviduct, vas deferent and epidydimis. PAX2 is thought to orchestrate the pattern of gene expression, including that of other PAX family members, also during other organ development. In humans, PAX2 heterozygous mutations, arising de novo or inherited in an autosomal dominant fashion, have been associated with renal coloboma syndrome (RCS) (OMIM 120330). Phenotypic features of the syndrome have been related to PAX2 haploinsufficiency. Haploinsufficiency deals with the notion that level of protein is critical to its correct function. RCS hallmarks are bilateral optic nerve coloboma and renal hypoplasia. The term coloboma includes developmental abnormalities of the optic nerve (ranging from mild optic disc dysplasia to optic nerve aplasia), retina, choroid and iris [1]. Renal hypoplasia is the most common renal abnormality (60% of patients). Oligomeganephronia, renal dysplasia or multicystic dysplastic kidney have also been reported [2–4]. Additional congenital anomalies may occur with variable penetrance and include: vesicoureteric reflux, which is detected in approximately 25% of patients, even though its frequency may be underestimated as it naturally improves with age; auditory anomalies, namely sensorineural deafness; skin and joint abnormalities, which occur in <20% of patients, and CNS anomalies. A significant degree of phenotypic variation may be observed, even between family members who share the same mutation [5]. Clinical features in humans strongly resemble those observed in PAX2 heterozygous mutant mice. The effects of PAX2 mutations have been studied through the development of three different PAX2 mutant mouse models: Krd, PAX2 and PAX2knockout mice. Homozygous carriers of the three different strains of PAX2 mutant mice died in embryonic stages (Krd), at birth or soon after (PAX2 and PAX2-knockout). Irrespective of the type of mutation, heterozygous mutant mice exhibited a broad range of renal phenotypes, from renal agenesis to mild affected or nearly normal urinary tract. They also showed retinal and optic nerve colobomatous changes, while genital tract was normal and CNS and ear might be unaffected. PAX2 mutations have also been reported in patients with renal hypodysplasia without eye anomalies [4,6,7]. No PAX2 gene complete deletion has yet been reported in the literature. Herein we describe a 6-year-old girl with an interstitial deletion of the long arm of chromosome 10, involving the entire PAX-2 locus. Correspondence and offprint requests to: Dr. Elisa Benetti, Nephrology, Dialysis and Transplant Unit, Department of Paediatrics, University of Padova, Italy. Email: elisabene@libero.it Nephrol Dial Transplant (2007) 22: 2076–2078