DiagnosisClinical DiagnosisThe diagnosis of renal coloboma syndrome (papillorenal syndrome) is based on clinical findings in the kidneys and eyes. Formal clinical diagnostic criteria have not been established.Renal findings Hypoplastic kidneys characterized on ultrasound examination by hypoplasia (small size for age) and hyperechogenicity [Schimmenti et al 1995]. Renal hypoplasia is usually bilateral, although marked variability between kidneys can be observed, e.g., one small or absent kidney and one of normal size. Renal hypodysplasia (RHD), characterized histologically by reduced number of nephrons, small kidney size, and disorganized renal tissue [Weber et al 2006]. Renal hypodysplasia was the most common renal finding in 114/173 (65%) of individuals with mutations [Bower et al 2012].Multicystic dysplastic kidney, characterized histologically by cystic or dysplastic kidneys, exhibiting some degree of disorganization of the kidney architecture. Multicystic dysplastic kidneys are observed in about 6%-10% of individuals with renal coloboma syndrome [Fletcher et al 2005, Bower et al 2012]. Oligomeganephronia is a pathologic finding characterized by fewer than normal glomeruli that are enlarged in size [Salomon et al 2001]. Note: Oligomeganephronia is not pathognomonic for renal coloboma syndrome. Renal insufficiency and end-stage renal disease (ESRD). Because most data are aggregated from individual case reports and small case series, the exact incidence of stage 5 chronic kidney disease requiring kidney transplantation is not precisely known. Of 53 individuals with mutations in whom the age at diagnosis for stage 5 CKD was reported, the mean age was 19.5 years (range: birth to 79 years) [Bower et al 2012].Vesicoureteral reflux was reported in 25/173 (14%) of individuals with mutations in a large literature review and case series [Bower et al 2012].Other renal anomalies in the congenital anomalies of the kidney and urinary tract (CAKUT). Each of the following findings in the CAKUT spectrum has been reported in fewer than five individuals with mutations: UPJ obstruction; medullary sponge kidney; horseshoe kidney; pyeloureteral duplication; and renal malrotation.Uncommon non-CAKUT renal findings. Nephrolithiasis (kidney stones) has been reported in several individuals; an intrarenal teratoma was reported in a single individual [Choi et al 2005, Bower et al 2012]. Eye findings The primary eye finding is dysplasia of the optic nerve, a phenotypic spectrum of optic nerve dysplasia that ranges from severe to mild. Abnormalities of the optic nerve have been identified in 125/173 (72%) of individuals with mutations [Bower et al 2012].The most severe form is characterized by an apparently enlarged disc in which the vessels that normally exit from the center of the disc, exit instead from the periphery [Schimmenti et al 2003]. Associated abnormalities may include deep excavation of the optic nerve head with redundant fibroglial tissue. A milder form is an optic nerve pit characterized by a relatively localized (or sub-total) excavation of the optic disc. The mildest form is the exiting of the retinal vessels from the periphery of the disc without malformation of the disc itself. Note: (1) Differences exist in the terminology used to designate dysplasia of the optic nerve with abnormal passage of retinal vessels from the periphery of the optic nerve head. Some ophthalmologists refer to this finding as congenital excavation of the optic nerve and others as "optic nerve coloboma." However, the use of the term coloboma can be confusing in this setting because coloboma usually refers to non-closure of the optic fissure during the seventh week of gestation, resulting in typical uveal colobomas (iris and retinal colobomas). The developmental mechanism underlying the optic nerve abnormalities observed in renal coloboma syndrome is under investigation in animal models. (2) Some have described one of the optic nerve findings in this syndrome as "morning glory anomaly," defined as a wide and deeply excavated optic nerve with a central glial tuft and all vessels exiting abnormally at the periphery of the nerve, giving the appearance of a morning glory flower. However, it is debated whether use of the term morning glory anomaly is appropriate to describe the optic nerve malformation in renal coloboma syndrome because it may be a misnomer for the dysplasia of the optic nerve typically seen in this syndrome. Retinal findings have been described in 23/173 (13%) of individuals with mutations. Retinal coloboma (defined as absence of retinal tissue in the nasal ventral portion of the retina resulting from failure of closure of the uveal tract) has been reported in six individuals with mutations. Other retinal findings reported include: abnormal retinal pigment epithelium, abnormal retinal vessels, macular anomalies, and chorioretinal degeneration.Less common associated eye malformations in individuals with documented mutations in PAX2 [Sanyanusin et al 1995, Schimmenti et al 1995, Schimmenti et al 1999, Amiel et al 2000, Dureau et al 2001, Schimmenti et al 2003, Bower et al 2012] include the following: Scleral staphyloma, defined as posterior bulging of the eye wall (sclera) is likely a secondary thinning of neural-crest-derived tissue in the area of the anatomically abnormal optic nerve head. Retinal thinning and myopia may be secondary to enlargement of the globe. Optic nerve cyst, a cystic dilatation of the optic nerve posterior to the globe, is observed by cranial imaging (e.g., MRI). The cyst likely results from incomplete regression of the primordial optic stalk, followed by accumulation of fluid in its potential space. Macular abnormalities including macular degeneration, hyperpigmentation of the macula, cystic degeneration of the macula, and papillomacular detachment have been reported in a limited number of affected individuals.Lens abnormalities including lens opacity and posterior lens luxation have been reported in one affected individual each. It is not clear whether these findings are coincidental or related to the PAX2 mutation.Note: (1) Some individuals with renal coloboma syndrome may not have vision loss and hence, examination of the fundus through a dilated pupil may be necessary to observe optic nerve abnormalities [Chung et al 2001]. (2) Iris coloboma has not been observed in persons with PAX2 mutations.Other findingsA wide range of non-renal and non-ophthalmologic findings have been reported in individuals with renal coloboma syndrome. Some of these findings, such as sensorineural hearing loss, fit with known patterns of PAX2 expression. Hearing loss is noted in approximately 7% of individuals with mutations. Other rarely reported findings include CNS malformations, developmental delay, hyperuricemia (gout), soft skin, joint laxity, and elevated pancreatic amylase.Prenatal findingsPrenatal renal findings have not been characterized in a systematic manner. Many individuals with mutations were born before comprehensive anatomic scans in the second trimester became common, while information about prenatal findings is missing from many case reports. Eighteen individuals with mutations have been reported to have prenatal ultrasound abnormalities including oligohydramnios/anhydramnios, cystic renal dysplasia, multicystic dysplastic kidneys, and renal hypoplasia [Bower et al 2012]. Seven fetuses with a confirmed PAX2 mutation and severe prenatal renal failure (Potter sequence) have been reported [Martinovic-Bouriel et al 2010, Bower et al 2012]. In addition, four cases of severe prenatal renal failure have been reported in families with renal coloboma syndrome in which the presence of the familial mutation could not be verified in the affected fetus [Ford et al 2001, Bower et al 2012]. In several instances, parents with mild renal disease had pregnancies with severe renal disease presenting in utero.Molecular Genetic TestingGene. PAX2 is the only gene in which mutations are known to cause renal coloboma syndrome. Evidence for locus heterogeneity. It is estimated that about half of individuals with classic findings of renal coloboma syndrome do not have a mutation identified by sequencing of PAX2 [Dureau et al 2001, Parsa et al 2001]. Thus, genetic heterogeneity is a possibility. Clinical testing Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found in Bower et al [2011] (full text).Table 1. Summary of Molecular Genetic Testing Used in Renal Coloboma SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency ¹ Test AvailabilityPAX2Sequence analysis Sequence variants ^{2~50% of patients with strictly defined renal hypodysplasia and abnormalities of the optic nerve 3~7% of patients presenting with apparently nonsyndromic renal hypodysplasia 4~23% of patients referred for PAX2 testing in clinical diagnostic laboratories 50% in patients with iris coloboma 6Clinical Deletion / duplication analysis 7Deletion of exon(s) or entire geneUnknown 8KaryotypingBalanced translocationOne case 91. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Dureau et al [2001]. PAX2 mutations were identified in 9/17 patients with renal hypodysplasia and optic nerve malformations.4. Nishimoto et al [2001], Salomon et al [2001], Weber et al [2006], Martinovic-Bouriel et al [2010], Thomas et al [2011]. PAX2 mutations were identified in 16/219 [7.3%] of probands in these 5 series of individuals presenting with renal hypoplasia. Ophthalmologic examination revealed abnormalities of the optic nerve in 10/16 of these individuals.5. Bower et al [2011]. Based on the reported experiences of laboratories in the United States, France, and New Zealand. Of 208 probands referred for analysis, 48 had mutations in PAX2. Individuals without a mutation referred for testing often had atypical findings such as iris coloboma.6. Iris coloboma has not been reported to date in individuals with PAX2 mutations. 7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.8. Three whole-gene deletions have been reported [Benetti et al 2007, Raca et al 2011, Hoefele et al 2012, Laimutis et al 2012]. These deletions involved between one and 90 additional genes beyond PAX2. MLPA analysis in two laboratories has not identified any instances in which whole-exon deletions within PAX2 were identified in individuals with RCS [Bower et al 2011, personal communication].9. A single individual with a de novo apparently balanced translocation with breakpoints within PAX2 has been reported [Narahara et al 1997]. Because the translocation was apparently balanced, it is not clear if it would have been detected by quantitative methods such as aCGH or MLPA.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. PAX2 molecular genetic testing should be considered in a proband who has eye findings and/or renal findings of renal coloboma syndrome. Sequence analysis should be performed first. If a disease-causing mutation is not identified, deletion/duplication analysis may be considered.Predictive testing for at-risk family members could be used to clarify the genetic status of at-risk relatives in order to begin expectant management of renal disease and/or eye disease. Predictive testing requires prior identification of the disease-causing mutation in an affected family member. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation in an affected family member. Genetically Related (Allelic) DisordersNishimoto et al [2001] suggested that the finding of apparently isolated renal hypoplasia in two of twenty (10%) probands with a PAX2 mutation represent allelic heterogeneity in PAX2 mutations (see Clinical Description). One of the affected individuals in the group was subsequently found to have eye malformations. Further studies have demonstrated that PAX2 mutations can be identified in cohorts of individuals with renal hypodysplasia. Weber et al identified seven individuals with mutations in six of 99 European families with congenital anomalies of the kidney and urinary tract (CAKUT), for a prevalence of 7% [Weber et al 2006]. In this group, five affected individuals had previously undiagnosed eye abnormalities. In a North American cohort of 73 probands, three with apparently nonsyndromic renal hypodysplasia were identified to have mutations in PAX2, for a prevalence of 4% [Thomas et al 2011].}

Natural HistoryRenal coloboma syndrome is characterized by hypodysplastic kidneys and optic nerve abnormalities (most commonly optic nerve dysplasia) with or without optic nerve or retinal coloboma [Schimmenti et al 2003].The clinical findings vary even within families, with some family members having either renal manifestations or optic nerve abnormalities and others having both. The severity of renal malformations can range within a family from absence of clinical symptoms to severe fetal renal failure.In some instances a detailed eye examination is necessary to reveal the ocular findings of renal coloboma syndrome in individuals presenting with characteristic renal findings. For example:In 20 probands ascertained for apparently isolated renal hypoplasia/dysplasia without known eye malformations, Nishimoto et al [2001] found PAX2 mutations in two — one of whom had eye findings consistent with renal coloboma syndrome on ophthalmologic examination. Of nine probands ascertained for oligomeganephronia by Salomon et al [2001], three were found to have a PAX2 mutation. On further evaluation all three with a PAX2 mutation were found to have minor eye findings consistent with renal coloboma syndrome; none had visual impairment. In an individual who had undergone renal transplantation for end-stage renal disease (ESRD), an optic nerve coloboma was found incidentally. Subsequently a mutation in PAX2 was identified [Chung et al 2001]. Conversely, in a family ascertained because of poor vision with optic disc abnormalities and abnormal optic disc vasculature, Parsa et al [2001] found renal hypoplasia in several members and previously unsuspected ESRD in one family member. Molecular genetic testing for PAX2 was carried out; no mutations were identified.Renal disease. Renal insufficiency/failure can occur at any age. Age at diagnosis of stage 5 chronic kidney disease ranges from birth to 79 years.The natural history of vesicoureteral reflux varies: in some individuals ureteral reimplantation has been required [Schimmenti et al 1995]; in others the reflux has spontaneously resolved [Ford et al 2001].Eye abnormalities. Impaired visual acuity of one or both eyes is present in 75% of affected individuals; acuity ranges from light perception only to normal. Other findings can include nystagmus, myopia, and strabismus. The natural history of visual acuity in individuals with renal coloboma syndrome has not been prospectively studied. In some instances, significant changes in visual acuity have been reported. Visual acuity deteriorated in one person as a result of retinal detachment [Ford et al 2001]. One person previously reported acute vision loss resulting in a change of visual acuity from 20/80 to light perception only [Schimmenti et al 1995]; however, the cause of vision loss was unexplained as there was no evidence of detachment or macular changes [Schimmenti, unpublished observation].Other. Less commonly reported findings in affected individuals include high-frequency hearing loss, soft skin, and ligamentous laxity.

Genotype-Phenotype CorrelationsSome authors have observed that mutations in exons 7-9 result in renal hypoplasia/dysplasia and milder ocular findings [Porteous et al 2000, Nishimoto et al 2001]. Others have argued that renal disease results from a haploinsufficiency mechanism, while ocular findings are the result of dominant negative effects [Benetti et al 2007]. Review of all reported cases to date does not reveal a consistent genotype/phenotype correlation. This is most dramatically illustrated by the tremendous variability in the severity of ocular and renal findings within families. To date, no clear evidence suggests that the location of a mutation (paired domain, octapeptide domain, partial homeodomain, or trans-activation domain) or the type of mutation (missense mutation, nonsense mutation, or gene deletion) consistently predicts the clinical phenotype.

Differential DiagnosisCHARGE syndrome. Renal dysplasia and retinal/optic nerve colobomas are major findings in CHARGE syndrome (coloboma, heart malformations, atresia choanae, retardation of growth and development, ear and hearing defects). Mutations in PAX2 were not identified in a small series of persons with CHARGE syndrome [Tellier et al 2000; Schimmenti, unpublished]. Sixty percent of individuals with CHARGE syndrome have mutations in or deletions of CHD7. Oligomeganephronia. Kidney phenotypes overlapping oligomeganephronia in renal coloboma syndrome have also been associated with branchiootorenal syndrome (EYA1 mutations) [Sikora et al 2001], chromosome 4p deletions (see Wolf-Hirschhorn syndrome), or ring chromosome 4 mosaicism; or found in association with diabetes mellitus in persons with HNF1B (TCF2) mutations [Bohn et al 2003]. Cat-eye syndrome. Colobomatous eye defects and kidney abnormalities are manifestations of cat-eye syndrome caused by tetraploid dosage of proximal 22q. PAX6 mutations. Eye phenotypes overlapping with renal coloboma syndrome have been reported in individuals with mutations in PAX6 (see Aniridia) [Azuma et al 2003]. COACH syndrome (cerebral vermis hypoplasia, oligophrenia, ataxia, optic nerve coloboma, hepatic fibrosis) [Verloes & Lambotte 1989, Gentile et al 1996] has overlapping findings. Persons with renal coloboma syndrome typically do not have developmental disability or hepatic findings. Joubert syndrome and related disorders (JSRD). Joubert syndrome is characterized by a distinctive cerebellar and brain stem malformation (the "molar tooth sign" seen on cranial MRI), hypotonia, developmental delays, and either episodic hyperpnea or apnea or atypical eye movements or both. Most children with Joubert syndrome develop truncal ataxia. Other features sometimes observed include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. To date mutations in one of the following eighteen genes are identified in about 50% of individuals with a JSRD: NPHP1, CEP290, AHI1, TMEM67 (MKS3), RPGRIP1L, CC2D2A, ARL13B, INPP5E, OFD1, TMEM216, KIF7, TCTN1, TCTN2, C5orf42, CEP41, TMEM138, TTC21B, and TMEM237; the other genes involved are unknown. Inheritance is autosomal recessive. In contrast to Joubert syndrome, renal coloboma syndrome does not typically include developmental disability. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with renal coloboma syndrome, the following are recommended:Evaluation of renal structure by renal ultrasound examination Measurement of renal function by serum electrolyte concentrations, BUN, and creatinine Urinalysis to evaluate for the presence of blood and protein Evaluation for vesicoureteral reflux, by voiding cytourethrogram (VCUG) if clinically indicated Dilated eye examination Audiologic assessment (See Deafness and Hereditary Hearing Loss Overview for details of audiologic assessment.) Genetics consultationTreatment of ManifestationsA team approach that includes specialists in ophthalmology, nephrology, medical genetics, and audiology is recommended. Management is focused on preventing complications of end-stage renal disease (ESRD) and/or vision loss resulting from retinal detachment. Treatment of hypertension and/or vesicoureteral reflux (if present) may preserve renal function. ESRD is treated with renal replacement therapy (i.e., dialysis and/or renal transplantation).Low vision experts can assist with adaptive functioning of those with significant vision loss. Prevention of Secondary ComplicationsPrevention of retinal detachment in those with congenital optic nerve abnormalities includes close follow up with an ophthalmologist and use of protective lenses. SurveillanceNo disease-specific guidelines have been developed. The following ongoing evaluations are recommended in all individuals in whom mutations have been confirmed.Follow-up by a nephrologist to monitor renal function and blood pressure Follow-up by an ophthalmologist to monitor vision. Any change in vision could indicate a retinal detachment and should be treated as a medical emergency. Evaluation of Relatives at RiskAt-risk relatives should be offered molecular genetic testing if a mutation in PAX2 has been identified in an affected family member. For those in whom a mutation in PAX2 cannot be identified, dilated ophthalmologic examination and renal ultrasound examination, tests of renal function, urinalysis, and blood pressure evaluation should be performed.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management It is important that a female who has a mutation have a thorough renal evaluation prior to becoming pregnant. Individuals with clinical renal disease should consult with appropriate professionals including nephrologists and maternal fetal medicine specialists to establish a plan for medical management during pregnancy. Pregnancies at 50% risk for renal coloboma syndrome should be monitored for fetal renal function. Comprehensive ultrasound in the second trimester is recommended to evaluate fetal renal anatomy. Ongoing monitoring for oligohydramnios in the second and third trimesters is recommended in at-risk pregnancies.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Renal Coloboma Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDPAX210q24​.31Paired box protein Pax-2PAX2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Renal Coloboma Syndrome (View All in OMIM) View in own window 120330PAPILLORENAL SYNDROME 167409PAIRED BOX GENE 2; PAX2Molecular Genetic PathogenesisThe pattern of abnormalities in renal coloboma syndrome is consistent with the known expression pattern of PAX2 during embryonic development. Porteous et al [2000] and Torban et al [2000] have demonstrated in mouse models and tissue culture that normal biallelic PAX2 expression is needed to prevent programmed cell death. Normal allelic variants. PAX2 contains 12 coding exons. Alternative splicing of this gene results in multiple transcript variants. The longest transcript variant NM_003990.3 has 11 exons. None of the known transcripts contains all 12 coding exons.Pathologic allelic variants. See Table 2 (pdf).Normal gene product. NM_003990.3 encodes a PAX-2 isoform of 431 amino acids (NP_003981.2). Paired box protein PAX-2 is a DNA-binding protein characterized by an N-terminal paired domain, a bipartite helix-loop-helix domain, a small octapeptide domain, a truncated homeodomain, and a proline/serine/threonine-rich C-terminal domain. Multiple isoforms, by alternative splicing of exons 6, 10, and 12, are known to exist. Abnormal gene product. The majority of PAX2 mutations are expected to result either the loss of expression from one allele or in expression of a significantly truncated protein. The most common recurring mutation is the c.76dup mutation, which has also been called c.619insG. This mutation results from the insertion of an extra guanine residue in a stretch of seven guanine residues and has been reported in 25 independent families. Nonsense, frameshift, and splice mutations have been reported in all four functional domains of PAX2.To date, all clearly pathogenic in-frame mutations (missense, in-frame deletions, and in-frame duplications) are located in the paired domain (exons 2-4). It is not known if these mutations exert their effect by reducing the binding to normal DNA targets or by allowing binding to abnormal DNA targets. Two missense mutations have been reported outside of the paired domain: p.(Thr368Ser) [NM_003988.3] and p.(Ser387Asn), but these mutations have not been clearly proven to be pathogenic.