GeneReviews^® [Internet].

Clinical characteristics.

PAX2-related disorder is anautosomal dominant disorder associated with renal and eye abnormalities. The disorder was originally referred to as renal coloboma syndrome and characterized by renal hypodysplasia and abnormalities of the optic nerve; with improved access to molecular testing, a wider range of phenotypes has been recognized in association with pathogenic variants inPAX2. Abnormal renal structure or function is noted in 92% of affected individuals and ophthalmologic abnormalities in 77% of affected individuals. Renal abnormalities can be clinically silent in rare individuals. In most individuals, clinically significant renal insufficiency / renal failure is reported. End-stage renal disease requiring renal transplant is not uncommon. Uric acid nephrolithiasis has been reported. Ophthalmologic abnormalities are typically described as optic nerve coloboma or dysplasia. Iris colobomas have not been reported in any individual withPAX2–related disorder. Ophthalmologic abnormalities may significantly impair vision in some individuals, while others have subtle changes only noted after detailed ophthalmologic examination. Additional clinical findings include high-frequency sensorineural hearing loss, soft skin, and ligamentous laxity.PAX2 pathogenic variants have been identified in multiplesporadic andfamilial cases of nonsyndromic renal disease including renal hypodysplasia and focal segmental glomerulosclerosis.

Diagnosis/testing.

The diagnosis ofPAX2-related disorder is established in aproband with the characteristic renal and/or eye findings by the identification of aheterozygouspathogenic variant inPAX2 bymolecular genetic testing. Among individuals with apparently nonsyndromic renal hypodysplasia and in families withautosomal dominantisolated focal segmental glomerulosclerosis, pathogenic variants inPAX2 have been identified in approximately 8% and 4%, respectively.

Management.

Treatment of manifestations: Ongoing treatment of hypertension and/or vesicoureteral reflux; renal replacement therapy (dialysis and/or renal transplantation) for end-stage renal disease; low vision aids for significant visual impairment.

Prevention of secondary complications: Use of protective eyewear to prevent retinal detachment.

Surveillance: Follow up by a nephrologist to monitor renal function and blood pressure and an ophthalmologist to monitor vision, with periodic audiometric evaluations.

Evaluation of relatives at risk: Offermolecular genetic testing if aPAX2pathogenic variant has been identified in an affected family member. If noPAX2 pathogenic variant has been found, perform dilated ophthalmologic examination, renal ultrasound examination, tests of renal function, uric acid levels, and urinalysis; measure blood pressure.

Genetic counseling.

PAX2-related disorder is inherited in anautosomal dominant manner. Approximately 65% of probands with a documentedPAX2pathogenic variant have a negative family history. In such cases, the negative family history may be explained by ade novo pathogenic variant, unrecognized symptoms in the parents, or parentalgermline mosaicism for aPAX2 pathogenic variant. Both maternal and paternal germline mosaicism, with unaffected parents having more than one affected child with a pathogenic variant, have been reported. Prenatal testing andpreimplantation genetic testing are possible if the pathogenicPAX2 pathogenic variant has been identified in the family.

Suggestive Findings

PAX2-related disordershould be suspected in individuals with the following clinical findings in thekidneys and/oreyes.

Note:PAX2 pathogenic variants are more likely to be identified in individuals with both ophthalmologic and renal involvement, but are increasingly recognized in cases withisolated renal findings such as renal hypodysplasia or focal segmental glomerulosclerosis [Barua et al 2014].

Establishing the Diagnosis

The diagnosis ofPAX2-related disorderis established in aproband with the characteristic renal and/or eye findings by the identification of aheterozygous pathogenic (orlikely pathogenic) variant inPAX2 onmolecular genetic testing (seeTable 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in thisGeneReview is understood to include likely pathogenic variants. (2) Identification of aheterozygousPAX2 variant ofuncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can includesingle-gene testing,chromosomal microarray analysis (CMA), use of amultigene panel, andmore comprehensivegenomic testing:

• Single-gene testing. Sequence analysis ofPAX2 is performed first and followed by gene-targeteddeletion/duplication analysis if nopathogenic variant is found.
• Chromosomal microarray analysis (CMA) – if not already performed – may be obtained to detect genome-wide deletions/duplications (includingPAX2).
  Note: A single case ofPAX2-related disorder with an apparently balancedde novo t(10;13)translocation with a breakpoint at thePAX2locus has been reported [Narahara et al 1997]. Because balanced rearrangements may not be detected by CMA,karyotype analysis could be considered in cases with a compelling clinicalphenotype and normalPAX2 sequencing andgene-targeteddeletion/duplication analysis.
• Amultigene panel that includesPAX2 and other genes of interest (seeDifferential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnosticsensitivity of the testing used for eachgene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in thisGeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants ofuncertain significance in genes that do not explain the underlyingphenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focusedexome analysis that includes genes specified by the clinician. (4) Methods used in a panel may includesequence analysis,deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels clickhere. More detailed information for clinicians ordering genetic tests can be foundhere.
• More comprehensivegenomic testing (when available) includingexome sequencing andgenome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a differentgene or genes that results in a similar clinical presentation).
  For an introduction to comprehensivegenomic testing clickhere. More detailed information for clinicians ordering genomic testing can be foundhere.

Clinical Description

PAX2-related disorder is associated with abnormalities involving the kidneys and/or the eyes. The originalPAX2-related disorder known as renal coloboma syndrome is characterized by hypodysplastic kidneys and optic nerve abnormalities (most commonly optic nerve dysplasia) with or without optic nerve or retinal coloboma [Sanyanusin et al 1995a,Schimmenti et al 1995,Schimmenti et al 2003].

Variability. 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 ofPAX2-related disorder in individuals presenting with characteristic renal findings [Chung et al 2001,Nishimoto et al 2001,Salomon et al 2001] or renal evaluation is needed in individuals with characteristic eye findings [Parsa et al 2001].

A wide range of kidney and eye findings can be found in individuals withPAX2-related disorder (seeSuggestive Findings).

Renal disease. Renal insufficiency/failure can occur at any age. The 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 withPAX2-related disorder 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 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. The age of onset and progression of hearing loss remain unknown and have not been evaluated prospectively. The hearing loss, when present, has been discovered in childhood and is bilateral high-frequency sensorineural hearing loss [Schimmenti et al 1995,Bower et al 2012].

Prenatalphenotype. Abnormalities including oligohydramnios/anhydramnios, cystic renal dysplasia, multicystic dysplastic kidneys, and renal hypoplasia were reported on prenatal ultrasound in 18 individuals withPAX2 pathogenic variants [Bower et al 2012]. Seven fetuses with a confirmedPAX2pathogenic variant and severe prenatal renal failure (Potter sequence) have been reported [Martinovic-Bouriel et al 2010,Bower et al 2012]. In several instances, parents with mild renal disease had pregnancies where the fetus presented with severe renal disease in utero.

Genotype-Phenotype Correlations

Review of all reported cases to date does not reveal a consistentgenotype/phenotype correlation. This is most dramatically illustrated by the tremendousintrafamilial variability in the severity of ocular and renal findings. To date, no clear evidence suggests that the location of apathogenic variant (paireddomain, octapeptide domain, partial homeodomain, or transactivation domain) or the type of pathogenic variant (missense variant,nonsense variant, orgenedeletion) consistently predicts the clinical phenotype.

Penetrance

Only one individual with apathogenic variant inPAX2 in whom renal and ophthalmologic examinations were performed and documented as normal has been reported [Bower et al 2012]. Thus,penetrance appears to be greater than 99%. In individuals with pathogenic variants inPAX2, the penetrance of eye malformations is at least 77% [Bower et al 2012]. This should be viewed as a minimum figure, as fully 21% of individuals withPAX2 pathogenic variants have not had a dilated eye examination to evaluate for subclinical abnormalities of the optic nerve. The penetrance for renal malformations or renal disease is at least 92%. Again, this figure should be viewed as a minimum, as some individuals with pathogenic variants have not had full renal evaluations.

Nomenclature

Terms previously used for renal coloboma (papillorenal syndrome) syndrome:

• Coloboma-ureteral-renal syndrome
• Optic nerve coloboma with renal disease
• Coloboma of the optic nerve with renal disease
• Optic coloboma-vesicoureteral reflux-renal anomalies

Controversy regarding the naming of this syndrome has caused confusion in the field. The condition was named renal coloboma syndrome based on the presence of kidney abnormalities and the optic nerve abnormalities described by the ophthalmologists who identified the original families found to havePAX2 pathogenic variants [Sanyanusin et al 1995a,Sanyanusin et al 1995b]. In 2001, Parsa et al identified a family with similar optic nerve and renal abnormalities where no variants inPAX2 were identified and suggested that the name of the condition be changed to papillorenal syndrome; it is unclear if the two entities are related.

Prevalence

The prevalence ofPAX2-related disorder is unknown. At the time of the most recent update, 243 affected individuals from 124 different families are recorded in thePAX2locus-specific database (www.lovd.nl/PAX2). There is no evidence for a significantfounder effect in any population.

Table 2.

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Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed withPAX2-related disorder, the following are recommended if they have not already been completed:

• 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 cystourethrogram (VCUG)
• Dilated eye examination
• Audiologic assessment (SeeGenetic Hearing Loss Overview for details of audiologic assessment.)
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A team approach that includes specialists in ophthalmology, nephrology, audiology, and clinical genetics is recommended.

Management is focused on preventing complications of end-stage renal disease (ESRD) and/or vision loss resulting from retinal detachment.

• Ongoing 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 Complications

Prevention of retinal detachment in those withcongenital optic nerve abnormalities includes close follow up with an ophthalmologist and use of protective eyewear.

Surveillance

No disease-specific guidelines have been developed. The following ongoing evaluations are recommended in all individuals withPAX2-related disorder.

• 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.
• Audiometric evaluation with periodic follow up

Agents/Circumstances to Avoid

Avoid the following:

• Use of medications known to affect renal function (requires consultation with a specialist in nephrology)
• Contact sports

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual bymolecular genetic testing of thePAX2pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic counseling purposes.

Pregnancy Management

It is important that a female withPAX2-related disorder 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.

Therapies Under Investigation

SearchClinicalTrials.gov in the US andEU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

PAX2-related disorder is inherited in anautosomal dominant manner.

Risk to Family Members

Parents of aproband

• Approximately 35% of individuals withPAX2-related disorder have a recognized clinically affected parent [Bower et al 2012]. Because tremendous variability in the severity of ocular and renal findings is observed within families, parents may be more or less severely affected than their offspring.
• Approximately 65% of probands withPAX2-related disorder representsimplex cases (i.e., a single occurrence in a family). Molecular testing in 23 (41%) of 56 simplex cases confirmed thede novo origin for thepathogenic variant, while parental testing was not performed in the remaining 33 cases [Bower et al 2012].
• Recommendations for the evaluation of parents of aproband with an apparentde novopathogenic variant includemolecular genetic testing for thePAX2 pathogenic variant identified in the proband.
• If thepathogenic variant found in theproband cannot be detected in the leukocyte DNA of either parent and/or neither parent has clinical findings consistent with a diagnosis ofPAX2-related disorder, possible explanations include ade novo pathogenic variant in the proband orgermline mosaicism in a parent. Both maternal and paternal germline mosaicism have been reported inPAX2-related disorder [Amiel et al 2000,Cheong et al 2007].
• Note: If the parent is the individual in whom thepathogenic variant first occurred, the parent may havesomatic mosaicism for the variant and may be mildly/minimally affected.
  Ophthalmologic abnormalities consistent withPAX2-related disorder have been reported in a parent without aPAX2pathogenic variant who had two children with aPAX2 pathogenic variant. It was hypothesized that this parent had somatic (andgermline)mosaicism, but the pathogenic variant was absent in the tissues analyzed (leukocytes, fibroblasts, oral mucosa) [Bower et al 2012].

Sibs of aproband. The risk to the sibs of the proband depends on the status of the proband's parents:

• If a parent of theproband is affected, the risk to the sibs is 50%.
• If the parents of aproband withPAX2-related disorder have been tested for thepathogenic variant identified in the proband and:
  • A parent of theproband has thePAX2pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of intrafamilial clinical variability, it is not possible to predict thephenotype in sibs who have inherited a pathogenic variant.
  • If thePAX2pathogenic variant found in theproband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parentalgermline mosaicism. Germline mosaicism, in which parents who test negative for thefamilialPAX2 pathogenic variant have more than one affected child, has been documented in two families [Bower et al 2012].

Offspring of aproband. Each child of an individual withPAX2-related disorder has a 50% chance of inheriting thePAX2pathogenic variant.

Other family members. The risk to other family members depends on the status of theproband's parents: if a parent is affected and/or has aPAX2pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

SeeEvaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic individuals. It is appropriate to considermolecular genetic testing of at-risk asymptomatic family members in order to guide vision and renal management (see Management,Surveillance). Molecular genetic testing can only be used for testing at-risk relatives if aPAX2pathogenic variant has been identified in an affected family member. Because early detection of at-risk individuals affects medical management, testing of individuals during childhood who have no symptoms is beneficial. It is appropriate to provide education andgenetic counseling for at-risk individuals younger than age 18 years and their parents prior to genetic testing.

Considerations in families with an apparentde novopathogenic variant. When neither parent of aproband with anautosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likelyde novo. However, non-medical explanations includingalternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offergenetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once thePAX2pathogenic variant has been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal andpreimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Prenatal fetal ultrasound examination of an at-risk pregnancy or known affected pregnancy may be used during the later stages of pregnancy to detect renal malformations and assess amniotic fluid volume, as findings could affect the well-being of the newborn or warrant further evaluation after birth.

Table A.

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Table B.

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Molecular Pathogenesis

The pattern of abnormalities inPAX2-related disorder is consistent with the known expression pattern ofPAX2 during embryonic development.Porteous et al [2000] andTorban et al [2000] have demonstrated in mouse models and tissue culture that normalbiallelicPAX2 expression is needed to prevent programmed cell death.

Gene structure.PAX2 contains 12 coding exons. Alternativesplicing of thisgene 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. SeeTable A,Gene for a detailed summary of gene and protein information.

Pathogenic variants. SeeTable A,Locus Specific. To date, nearly 90 different pathogenic variants have been reported in thePAX2 coding exons and adjoiningintronic sequences [Bower et al 2012].

Frameshift variants are the most common type;nonsense andmissense variants,splice site changes, andin-frame duplications have also been reported. Pathogenic variants tend to cluster in the paireddomain (exons 2-4), the homeodomain (exon 7), and the 5' portion of the transactivation domain (exon 8). A limited number of missense variants have been reported in exons 9-12, but the pathogenicity of these variants is not clearly established. A small number ofgenomic deletions and rearrangements have been reported. Partial-gene deletions are not a common pathogenic mechanism [Karger et al 2013].

The most common recurringpathogenic variant, c.76dupG (previously called c.619insG), is aduplication of a G residue in a stretch of seven Gs and has been reported in more than 25 independent families.

Normalgene 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 paireddomain, a bipartite helix-loop-helix domain, a small octapeptide domain, a truncated homeodomain, and a proline/serine/threonine-rich C-terminal domain. Multipleisoforms, by alternativesplicing of exons 6, 10, and 12, are known to exist.

Abnormalgene product. Review of ExAC (exac.broadinstitute.org) indicates that PAX2 is relatively intolerant of loss of function ormissense alleles. The majority ofPAX2 pathogenic variants are expected to result either in the loss of expression from oneallele or in expression of a significantly truncated protein.

To date, all clearly pathogenicin-frame variants (missense, in-frame deletions, and in-frame duplications) are located in the paireddomain (exons 2-4). It is not known if these pathogenic variants exert their effect by reducing the binding to normal DNA targets or by allowing binding to abnormal DNA targets. Six missense variants have been reported outside of the paired domain. Each of these variants has been reported in a single individual and the evidence for pathogenicity is not as strong as with otherPAX2 variants.

Revision History

• 14 August 2025 (aa) Revision:SIX5 removed as causative variant of branchiootorenal spectrum disorder (Differential Diagnosis)
• 8 February 2018 (ha) Comprehensive update posted live
• 20 November 2014 (me) Comprehensive update posted live
• 12 July 2012 (me) Comprehensive update posted live
• 8 June 2007 (me) Review posted live
• 8 December 2006 (las) Original submission

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