#120330
ICD+
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| PAPILLORENAL SYNDROME | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| RENAL-COLOBOMA SYNDROME OPTIC NERVE COLOBOMA WITH RENAL DISEASE COLOBOMA OF OPTIC NERVE WITH RENAL DISEASE OPTIC COLOBOMA, VESICOURETERAL REFLUX, AND RENAL ANOMALIES RENAL-COLOBOMA SYNDROME WITH MACULAR ABNORMALITIES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| RENAL HYPOPLASIA, ISOLATED, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because the papillorenal syndrome can be caused by heterozygous mutation in the PAX2 gene (167409) on chromosome 10q. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Papillorenal syndrome is an autosomal dominant disorder characterized by both ocular and renal anomalies, but may also include vesicoureteral reflux, high frequency hearing loss, central nervous system anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development (summary by Eccles and Schimmenti, 1999). Eye anomalies in this disorder consist of a wide and sometimes excavated dysplastic optic disc with the emergence of the retinal vessels from the periphery of the disc, designated optic nerve coloboma or 'morning glory' anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst, microphthalmia, and pigmentary macular dysplasia. The kidneys are small and abnormally formed (renal hypodysplasia), and have fewer than the normal number of glomeruli, which are enlarged (oligomeganephronia). These ocular and renal anomalies result in decreased visual acuity and retinal detachment, as well as hypertension, proteinuria, and renal insufficiency that frequently progresses to end-stage renal disease (summary by Schimmenti, 2011). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rieger (1977) reported a family in which the father showed bilateral optic disc anomalies and died of chronic nephritis; his son showed macular and retinal abnormalities but renal function was normal, whereas his daughter had normal eyes but suffered from renal failure. This is a variability not unexpected for an autosomal dominant syndrome. Karcher (1979) described a father and son with the 'morning glory' optic disc anomaly and renal disease. Weaver et al. (1988) reported 2 brothers with optic nerve colobomas associated with renal disease. There is uncertainty as to whether the 'morning glory' syndrome represents a colobomatous defect or an abnormality of regression of mesodermal structures of the embryonic optic disc (Kindler, 1970; Dempster et al., 1983). Under the designation papillorenal syndrome, Bron et al. (1989) described the same disorder. Parsa (1998) also concluded that this is a condition of dysplastic discs rather than coloboma and that papillorenal syndrome is a more appropriate designation. Schimmenti et al. (1995) and Sanyanusin et al. (1995) described a father and 3 sons had optic nerve colobomas, vesicoureteral reflux, and renal anomalies. The 35-year-old father was more mildly affected than the sons. He had bilateral optic nerve colobomas but no renal problems recognized during childhood. An evaluation prompted by the renal problems in his sons demonstrated hypertension, mild proteinuria, and an elevated serum creatinine, but normal renal ultrasound. Ophthalmologic examination showed severe bilateral myopia, scleral staphyloma, and bilateral colobomas. Mild sensorineural hearing loss of unknown cause was also present. The oldest affected son, aged 15 years, had chronic renal failure and severe visual impairment. He first presented at 18 months for investigation of short stature. He already had renal insufficiency and showed a nonfunctioning right kidney and bilateral grade IV vesicoureteral reflux. The last ureteral reimplantation was performed at age 2. Hearing was normal. The second affected son, aged 10 years, had severe visual impairment, optic nerve colobomas, and mild renal dysfunction. He had grade II vesicoureteral reflux and small hypoplastic kidneys with poor corticomedullary differentiation. The third affected son, aged 6 years, had progressive renal failure for which he underwent renal transplantation at the age of 5 years. Sanyanusin et al. (1995) reported further on 2 brothers with 'typical renal-coloboma syndrome without associated vesicoureteric reflux' who were originally described by Weaver et al. (1988). The younger brother had presented with severe progressive renal failure leading to renal transplantation and had a bilateral visual field defect with optic nerve colobomas. The older brother presented with chronic mild renal failure, a visual field defect, and optic nerve colobomas. The 2 brothers were the only affected family members and both parents had normal ophthalmologic examinations. Amiel et al. (2000) described a family in which 3 affected sibs showed striking ocular phenotypic variability. One sib had bilateral renal hypoplasia and 'morning glory' syndrome, whereas the other 2 presented with isolated unilateral cystic renal hypoplasia with no obvious ocular manifestation. Careful ophthalmologic examination of the latter 2 sibs showed an optic disc anomaly in both: bilateral papillary dysplasia in one and bilateral optic nerve coloboma in the other. Schimmenti et al. (1999) described a severely affected girl and a mildly affected mother and daughter, all of whom had PAX2 homoguanine tract (7G) missense mutations. The mother and daughter had optic nerve colobomas and the daughter had vesicoureteral reflux. The severely affected girl developed renal failure and had bilateral colobomatous eye defects. Additionally, this girl developed hydrocephalus associated with platybasia and a Chiari-1 malformation. Thus, the phenotype associated with PAX2 mutations must be expanded to include brain malformations. Amiel et al. (2000) described a family in which 3 affected sibs showed striking ocular phenotypic variability. One sib had bilateral renal hypoplasia and 'morning glory' syndrome, whereas the other 2 presented with isolated unilateral cystic renal hypoplasia with no obvious ocular manifestation. Careful ophthalmologic examination of the latter 2 sibs showed an optic disc anomaly in both: bilateral papillary dysplasia in one and bilateral optic nerve coloboma in the other. To define better the characteristics of the papillorenal syndrome, Parsa et al. (2001) studied 2 unrelated probands and 11 family members via Doppler imaging of the optic nerves and kidneys, fluorescein angiography, and genetic testing for PAX2 mutations. Affected individuals had numerous cilioretinal vessels with rudimentary or absent central retinal vessels. Static superonasal visual field defects, typical of papillorenal syndrome, corresponded to inferotemporal areas of anomalous retinal and choroidal perfusion and hypoplastic retina. Renal hypoplasia was discovered in 2 affected members of 1 family (with previously unsuspected renal failure in 1 case), and recurrent pyelonephritis was discovered in 4 affected members of the other family. No PAX2 mutations were detected in either family. In the papillorenal syndrome, the hereditary absence of the central retinal vessels may be missed, leading to confusion with isolated optic nerve coloboma, low-tension glaucoma, and morning glory anomaly. Parsa et al. (2001) suggested that greater awareness of this syndrome would avoid unneeded glaucoma therapy, allow earlier recognition of renal diseases, and facilitate genetic counseling. They proposed that the papillorenal syndrome is a primary vascular dysgenesis affecting the optic nerve, kidney, and urinary tract, causing hypoplasia of these structures. The authors concluded that the absence of mutations in the PAX2 gene in these families suggests that defects in other genes may also result in this syndrome. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a father and 3 sons with coloboma of the optic nerve and renal disease, Sanyanusin et al. (1995) identified a mutation in the PAX2 gene (167409.0001). In 2 brothers with optic nerve coloboma and renal disease originally described by Weaver et al. (1988), Sanyanusin et al. (1995) identified a heterozygous mutation in the PAX2 gene (619insG; 167409.0002). Cunliffe et al. (1998) studied 99 patients with isolated colobomas or colobomas and urogenital abnormalities. A gene mutation in the PAX2 gene was found in only 1 individual who had typical renal-coloboma syndrome. In a severely affected girl and a mildly affected mother and daughter, Schimmenti et al. (1999) identified mutations in the PAX2 gene. The mother and daughter had a contraction in a string of 7 G's to 6 G's on one allele of PAX2, leading to a premature stop codon 2 amino acids downstream. The severely affected girl, who also had a brain malformation, had an expansion to 8 G's on one allele, leading to a premature stop codon 27 amino acids downstream. The 8G expansion had been found in other patients without brain anomalies and had occurred spontaneously in a mouse model, PAX2(1Neu). In 3 sibs with papillorenal syndrome who showed striking ocular variability, Amiel et al. (2000) identified the PAX2 619insG mutation (167409.0002). The unaffected parents did not carry the mutation, suggesting the presence of germline mosaicism. The study of a PAX2 intragenic DNA microsatellite marker showed that the mutation was of paternal origin (false paternity was excluded by the study of polymorphic markers). Ford et al. (2001) described a family in which at least 7 members had manifestations of renal-coloboma syndrome. Two of these had renal disease due to oligohydramnios and renal hypoplasia, diagnosed prenatally by ultrasound examination. All affected members had the PAX2 619insG mutation (167409.0002). There was remarkable variability in both the ocular and renal manifestations. In a child with atypical bilateral optic nerve coloboma and congenital renal hypoplasia, Chung et al. (2001) identified a novel heterozygous PAX2 mutation leading to a prematurely truncated protein. The mutation was not found in the parents. The authors concluded that the causal relationship between PAX2 gene mutations and the renal-coloboma syndrome was further supported by this novel mutation. In a mother and daughter previously reported by Naito et al. (1989) with macular abnormalities accompanied by anomalies of the optic disc and kidney consistent with the diagnosis of renal-coloboma syndrome, Higashide et al. (2005) identified a mutation in the PAX2 gene (167409.0012). Higashide et al. (2005) suggested that this mutation might also cause foveal hypoplasia and pigmented macular atrophy in addition to anomalies of the optic disc and kidney. Because the daughter also had polydactyly, Naito et al. (1989) had made the diagnosis of acrorenoocular syndrome (607323). Isolated Renal Hypoplasia To investigate whether PAX2 mutations occur in patients with isolated renal hypoplasia, Nishimoto et al. (2001) analyzed DNA from 20 patients with bilateral renal hypoplasia associated with decreased renal function. Heterozygous PAX2 mutations were detected in 2 patients (167409.0010 and 167409.0011, respectively). Ophthalmologic examination revealed very mild, asymptomatic coloboma in the second patient, whereas the fundus was normal in the first. The mutation cosegregated with renal hypoplasia in the family of the first patient, appearing de novo in the patient's mother. Nishimoto et al. (2001) concluded that isolated renal hypoplasia can be part of the spectrum of the renal-coloboma syndrome. Martinovic-Bouriel et al. (2010) analyzed the PAX2 gene in 2 fetuses with renal anomalies and optic nerve colobomas and in 18 fetuses with isolated renal disease, of which 10 had uni- or bilateral renoureteral agenesis, 6 had enlarged dysplastic kidneys, and 2 had small dysplastic kidneys. In the 2 fetuses with papillorenal syndrome, the authors identified a frameshift and a splice site mutation in the PAX2 gene, respectively, but no mutations were detected in the 18 fetuses with isolated renal disease. Reviews Eccles and Schimmenti (1999) reviewed the clinical features of patients with renal-coloboma syndrome and PAX2 mutations, and the specific mutations reported to that time. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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