Papillorenal Syndrome

A number sign (#) is used with this entry because the papillorenal syndrome (PAPRS) is caused by heterozygous mutation in the PAX2 gene (167409) on chromosome 10q24.

Description

Papillorenal syndrome is an autosomal dominant disorder characterized by both ocular and renal anomalies. Less common findings include high frequency hearing loss, central nervous system anomalies, soft skin, ligamentous laxity, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development (summary by Eccles and Schimmenti, 1999; Negrisolo et al., 2011). The disorder shows wide inter- and intrafamilial variability. The renal features are part of a spectrum of malformations termed congenital anomalies of the kidney and urinary tract (CAKUT; see, e.g., 610805), and some patients with PAX2 mutations may present with CAKUT without obvious ocular abnormalities. In these patients, ocular abnormalities may be subtle and difficult to detect without advanced screening methods or may be normal (summary by Negrisolo et al., 2011; Iatropoulos et al., 2012).

Eye anomalies associated with PAX2 mutations 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.

Clinical Variability

Weber et al. (2006) identified heterozygous PAX2 mutations in 7 patients from 6 unrelated families ascertained for renal hypodysplasia. The families were part of a larger cohort of 99 index patients with renal hypodysplasia screened for mutations in 5 genes. Ocular abnormalities, including coloboma and optic disc dysplasia, were found in 5 of the 7 patients and in 1 of 2 affected parents. In most of these patients, the ocular alterations were so subtle that they had not been diagnosed before the detection of the PAX2 mutation.

In 2 of 20 unrelated children and young adults with CAKUT resulting in renal failure and renal transplantation but with no apparent ocular abnormalities, Negrisolo et al. (2011) identified 2 different de novo heterozygous mutations in the PAX2 gene: a nonsense mutation and a splice site mutation respectively. One of the patients was later found to have myopia and isotropy of the right eye. The other patients showed bilateral excavation of the optic disc on optic fundus reexamination. Negrisolo et al. (2011) concluded that patients with CAKUT without apparent ocular abnormalities should be screened for mutations in the PAX2 gene, and that ocular abnormalities may be underdiagnosed in patients with PAX2 mutations.

Thomas et al. (2011) identified heterozygous pathogenic PAX2 mutations in 3 of 73 children with chronic kidney disease due to renal hypodysplasia. It was not known if the patients with PAX2 mutations had subtle ocular findings, and Thomas et al. (2011) concluded that they should be followed for extrarenal manifestations. The findings also had implications for genetic counseling.

Iatropoulos et al. (2012) reported a pair of monozygotic twin sisters with papillorenal syndrome confirmed by genetic analysis who were discordant for the phenotype. The proband was found to have multicystic kidneys antenatally and she had poor renal function after birth. Renal examination showed a nonfunctional multicystic right kidney and a hyperechogenic left kidney with poor corticomedullary differentiation. She had chronic renal disease and underwent successful kidney graft at age 23. Dilated eye examination showed no ocular abnormalities. Her sister showed renal insufficiency at birth associated with hyperechoic renal pyramids, but this resolved rapidly. At age 10 years, dipstick showed mild proteinuria. At age 2 years, she had complete loss of visual acuity in the left eye due to optic nerve coloboma; the right eye was normal. At age 20 years, she had overt nephropathy with normal renal function. Both sisters had joint laxity and skin hyperextensibility. There was no evidence of somatic mosaicism for the mutation among tissues from the sisters, and Iatropoulos et al. (2012) postulated environmental or epigenetic modifiers to explain the discordant phenotype.

Barua et al. (2014) reported 7 unrelated individuals with CAKUT diagnosed in early childhood. Features were variable, and included solitary kidney with hydronephrosis or hydrocele, horseshoe kidney, ureteropelvic junction obstruction (UPJO), ureterovesical junction obstruction (UVJO), and vesicoureteral reflux (VUR). Two patients had additional nonrenal manifestations, including dysmorphic features. No ocular or auditory abnormalities were documented.

Pathogenesis

Parsa et al. (2002) noted that the dysplastic discs seen in papillorenal syndrome are not true colobomas: defective angiogenesis, rather than abnormal fissure closure, underlies the anomalous disc morphology as well as the retinal and choroidal hypoplasia with corresponding visual field defects. Affected individuals show multiple cilioretinal vessels and a variable attenuation or absence of the central retinal vessels. Alterations in vascular development also explain observed abnormalities of the renal cortex, the second most perfused tissue per gram of weight in the human body (after the choroid).

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.

Tellier et al. (1998) reported patients with isolated renal hypoplasia and mutation in the PAX2 gene (e.g., 167409.0005).

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 premature termination of the 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).

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.

Barua et al. (2014) identified 8 different missense mutations in the PAX2 gene in 7 (8%) of 85 individuals with CAKUT. Seven patients had a heterozygous mutation, whereas 1 patient with a more severe phenotype and extrarenal abnormalities was compound heterozygous. Parental DNA available from 3 of the patients showed that the mutations occurred de novo. Functional studies of the variants were not performed, but 6 occurred in the transactivation domain.

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.

Bower et al. (2012) reviewed published cases of PAX2 mutations as well as data from a consortium of 3 laboratories, and identified a total of 53 unique PAX2 mutations and 12 other PAX2 variants in 173 individuals from 86 families. The most frequently reported recurring mutation was 76dup (167409.0002). Renal disease was the most highly penetrant feature in this series, being identified in 159 (92%) of 173 mutation-positive individuals. The most common renal findings were renal hypodysplasia (114 patients; 65%), vesicoureteral reflux (25 patients; 14%), renal cysts (13 patients; 8%), and multicystic dysplastic kidneys (7 patients; 6%). Nineteen individuals (13%) were reported to have 'renal failure' without further details. In this series, 134 (77%) of 173 mutation-positive individuals were reported to have ophthalmologic abnormalities, whereas 12 (7%) had a normal eye exam and 37 (21%) did not have an eye exam. Abnormalities of the optic nerve were noted in 125 cases, with the most common findings described as optic nerve coloboma (84 patients), optic disc dysplasia (21), excavation of the optic disc or 'pits' (14), optic disc hyperplasia (11), morning glory optic discs (10), and hypoplastic optic discs (7). Additional findings included gliosis of the optic nerve and absent optic nerve head; several patients had more than 1 finding involving the optic nerve. Many patients had involvement outside the optic nerve, with retinal findings in 23 patients that included retinal coloboma (6), abnormal retinal pigment epithelium (6), abnormal retinal vessels (8), chorioretinal degeneration (3), and 1 report each of retinal detachment, retinal staphyloma, and retinal edema. Macular abnormalities were reported in 6 patients: macular degeneration, papillomacular detachment, hyperpigmentation of the macula, and cystic degeneration of the macula. Lens abnormalities were reported in 2 cases (posterior lens luxation and lens opacity), and microphthalmia was reported in 3 cases. Bower et al. (2012) noted that iris coloboma did not appear to be a feature in the renal coloboma syndrome, as it was not found in any of the mutation-positive individuals. Additional nonrenal, nonophthalmologic findings included hearing loss in 12 (7%) of the 173 patients. No clear genotype/phenotype correlations emerged from this study, and the authors commented that the tremendous intrafamilial variability described in renal coloboma syndrome suggests that factors other than PAX2 genotype play a significant role.