Nephrol Dial Transplant (2002) 17: 166-168
© 2002 European Renal Association-European Dialysis and Transplant Association
Teaching Point
An eye for the diagnosis of chronic renal failure in young patients
(Section Editor: K. Kühn)
1 Hull and East Yorkshire Hospitals NHS Trust, Hull Royal Infirmary, Kingston upon Hull, UK 2 Statewide Renal Services, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia
Keywords: dysplasia; eye examination; optic disc; PAX2; renal coloboma syndrome; renal failure
Introduction
Patients often present to nephrologists with end-stage renal dysfunction of an uncertain aetiology. Attention to other clinical findings may elucidate a diagnosis of a hereditary nephritis. This is important for both prognosis and screening of siblings and relatives, with potential earlier identification and treatment of renal disease.
Case report
A 3-year-old boy, who had ‘stale’ urine noted by his mother from the age of 6 months, was found to have vesico-ureteric reflux grade V. He underwent bilateral ureteric re-implantation at age 3.5 years. He remained asymptomatic until age 8 years when he was found to be hypertensive. Renal ultrasound and DMSA scans revealed bilateral renal hypoplasia with poor corticomedullary differentiation and chronic scarring. His plasma urea was 5.9 mmol/l and serum creatinine 0.13 mmol/l, with an estimated creatinine clearance of 55 ml/min. His karyotype was 46 XY.
By 13 years of age his renal function had deteriorated further (creatinine 0.32 mmol/l, urea 12.8 mmol/l and estimated creatinine clearance of 18 ml/min). His hypertension was controlled on medication (110/60 mm&!thinsp;Hg). Urinalysis was positive for moderate protein (2.4 g/day) and blood. His IQ was within the normal range although there was a history of behavioural problems at school. His weight was on 50th centile and his height between the 25th and 50th centile. His creatinine continued to rise reaching 0.72 mmol/l (7 ml/min) by the age of 15 years. He was noted to have some impairment of vision of the left eye. Routine eye examination revealed a malformation of the left anterior segment of the eye consistent with an optic disc coloboma, suggesting a diagnosis of renal coloboma syndrome. At age 16 years he commenced haemodialysis (creatinine 1.41 mmol/l, creatinine clearance 5 ml/min). Unfortunately 5 months after commencing haemodialysis he died from tricuspid valve endocarditis with multiple septic pulmonary emboli. His PAX2 gene mutation was not identified prior to his premature death.
Investigation of the family has revealed an 18-year-old sister with renal impairment (creatinine 0.12 mmol/l, measured creatinine clearance 48 ml/min), vesico-ureteric reflux, moderate proteinuria (2.6 g/day), hypertension and bilateral retinal colobomata. She has normal intelligence and a normal physical examination except for bilateral retinal colobomata, which at present have not caused any visual impairment. Their mother also has renal impairment and retinal coloboma. She is virtually blind with a most recent creatinine of 0.26 mmol/l.
Discussion
Renal coloboma syndrome is a recently described autosomal dominant disorder caused by mutations in the PAX2 gene [1]. The syndrome presents with variable abnormalities in optic nerve and renal development. These include optic disc dysplasia, optic nerve colobomas, vesico-ureteric reflux and renal hypoplasia [2–4]. In addition to these congenital anomalies, some patients with PAX2 mutations may have associated auditory, central nervous system, skin and joint anomalies [2]. Renal coloboma syndrome classically comprises proteinuric renal failure and coloboma of the eye (Figures 1
and 2). Of all the phenotypic abnormalities associated with PAX2 mutations, bilateral optic nerve colobomas and renal hypoplasia, with or without renal failure have the highest frequency of occurrence [4].
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Weaver and colleagues in 1988 first reported optic nerve coloboma associated with renal disease in two brothers [5]. Prior to this Reiger [6] had reported a father with optic disc anomalies and chronic nephritis, a son with macular and renal anomalies and a daughter with renal failure and normal eyes, while Karcher described a father and son with ‘morning glory’ disc anomaly and renal disease [7]. From genetic studies of a family, renal coloboma syndrome was linked with mutations in the PAX2 gene [1]. All affected family members were found to have a single nucleotide deletion in exon 5 resulting in a frameshift mutation of the PAX2 coding region and a truncated protein. The unaffected members of the family did not have this mutation. After analysis of several paternal relatives it was concluded that mutations may arise de novo.
PAX genes are a family of nine known paired box class DNA binding proteins that encode nuclear transcription factors believed to have a critical role in embryogenesis [8]. PAX2 is expressed in the optic vesicle, retina, otic vesicle, semicircular canals, mesonephros, metanephros, adrenals, spinal cord and hindbrain [9]. Based on this expression pattern, the phenotype caused by mutations of the PAX2 gene should consist of eye malformations, sensorineural hearing loss and renal anomalies. From screening 33 patients with a variety of renal anomalies, including renal coloboma syndrome, CHARGE (colobomas, heart anomalies, choanal atresia, retardation, genitourinary anomalies and ear anomalies) association and isolated renal hypoplasia, for mutations in the PAX2 gene, three different mutations in the PAX2 gene were identified (Table 1). No PAX2 mutation has been found in CHARGE association patients. This demonstrated that PAX2 mutations could be responsible for renal hypoplasia with or without various anomalies of ocular development [9]. Interestingly patients with ocular coloboma in isolation or in association with non-renal anomalies do not appear to have mutations of the PAX2 gene [10].
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Ten different mutations in the PAX2 gene have been identified (Table 1
) [3–4,9,13,14]. Patients with these mutations exhibit a variety of congenital anomalies. Patients who share the same PAX2 mutation show a significant degree of variation in clinical features [2]. The predominant abnormalities associated with PAX2 mutations are bilateral optic nerve colobomas and renal hypoplasia with or without renal failure [4]. Additional congenital anomalies that occur with variable penetrance include vesico-ureteric reflux, auditory anomalies, central nervous system anomalies and skin and joint anomalies. Although the PAX2 gene is essential for normal kidney development, its direct effects on kidney cell phenotype are uncertain but may effect the actions of vimentin and cytokeratin [11] or may be associated with increased apoptosis and reduced branching of the ureteric bud [12].
Teaching points
- (1) Renal coloboma syndrome is a potentially easily recognizable cause of renal failure and can be identified by careful eye examination of young patients who present with proteinuria and renal disease, especially with a history of reflux.
- (2) Family members can be easily screened through eye examination and estimation of renal function.
- (2) Family members can be easily screened through eye examination and estimation of renal function.
Notes
Supported by an educational grant from
Correspondence and offprint requests to: Samantha Hocking, 5/557-561 Mowbray Road, Lane Cove NSW 2066, Australia. Email: Samantha_L_Henry{at}hotmail.com 
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