Papillorenal syndrome (PRS) is a congenital autosomal dominant genetic disorder that affects the development of the kidneys and eyes. It is typically characterized by renal hypoplasia and optic nerve dysplasia.
Alternative names include renal coloboma syndrome (RCS), PAX2-related disorder, and coloboma-ureteral-renal syndrome.
History: First described by Rieger in 1977, formally named by Weaver et al. in 1988. In 1995, Sanyanusin et al. identified PAX2 gene mutations2).
Epidemiology: The exact prevalence is unknown, with 268 individuals registered in the PAX2 database of the Human Variome Project and fewer than 200 cases reported in the literature2). It is estimated that approximately 10% of children with unilateral or bilateral renal hypoplasia have PAX2 gene point mutations1). No racial or ethnic predilection has been reported.
The exact prevalence is unknown, with 268 registrations in the PAX2 database and fewer than 200 cases reported in the literature. Since about 10% of children with renal hypoplasia have PAX2 mutations, it is often discovered during detailed examination of kidney disease.
Ocular Findings
Optic disc dysplasia: The most common ocular finding. Characterized by central excavation, tortuous retinal vessels emerging from the periphery, and peripheral retinal thinning.
Optic nerve coloboma: Deep excavation of the optic disc. May resemble morning glory syndrome.
Others: microphthalmia, retinal coloboma, macular abnormalities, optic pit, optic nerve cyst. Iris coloboma is not associated with this syndrome.
Renal Findings
Renal hypoplasia: The most common renal symptom. Usually bilateral and present in 65% of affected individuals.
Histological changes: Fewer glomeruli than normal, glomerular hypertrophy, glomerulosclerosis, multiple cysts.
End-stage renal disease (ESRD): Mean age at diagnosis 19.5 years. Adult-onset focal segmental glomerulosclerosis (FSGS) has also been reported2).
Extraocular and extrarenal findings (rare): High-frequency sensorineural hearing loss (7%), CNS malformations (including Chiari I malformation), developmental delay, autism, short stature, and joint ligament laxity have been reported1).
OCT/Imaging findings: OCT may show intraretinal fluid accumulation or epiretinal membrane 2). Ultrasound can detect a defect at the level of the optic disc in the posterior eye (vitreous hernia) 1).
Visual acuity varies widely, from normal to light perception only. In mild optic disc dysplasia, normal vision may be preserved, but 75% of patients report some visual impairment. Severe cases can lead to profound vision loss.
PAX2 gene: Located on chromosome 10q24, mutations are found in about 50% of patients. It encodes a transcription factor protein essential for embryonic development of the eyes, kidneys, ears, brain, and spinal cord, and is a member of the paired-box transcription factor family 1).
Mutation mechanism: Haploinsufficiency or abnormal protein production due to missense mutations are pathogenic. Homozygous mutations are considered perinatally lethal. Reported mutation types include frameshift mutations (e.g., c.76dupG, p.Val26Glyfs*28) and microdeletions of exon 4 2, 4).
Inheritance pattern: Autosomal dominant inheritance, but about 65% of cases have no family history, suggesting de novo mutations or parental germline mosaicism. PRS can occur even without PAX2 mutations (possible polygenic disease).
Other risk factors:
The differential diagnosis from major diseases is shown below.
CHARGE syndrome
Gene: CHD7 gene mutation
Characteristic differences: Combination of coloboma, heart malformation, choanal atresia, developmental delay, genital hypoplasia, and ear abnormalities. Craniofacial malformations and cognitive abnormalities are points of differentiation from PRS1).
Joubert syndrome
Main differences: Coloboma and renal dysplasia are present, but developmental disability, cerebellar hypoplasia, and cerebellar dysfunction are observed. These findings are absent in PRS1).
Other differential diagnoses:
It cannot be ruled out. PAX2 mutations are detected in only about 50% of patients, and SNP microarrays or exome sequencing may miss microdeletions. Additional testing with whole genome analysis may be useful; if clinical findings are typical, a negative genetic test should not exclude the diagnosis 4).
There are currently no specific drugs or gene therapies for PRS. Treatment focuses on preventing and managing complications.
Blood pressure control, treatment of vesicoureteral reflux, and avoidance of nephrotoxic drugs can slow the progression of chronic kidney failure. When ESRD is reached, dialysis or kidney transplantation is chosen. Regular renal function monitoring is essential.
PAX2 is a member of the paired-box transcription factor family located on chromosome 10q24 and is one of the most important genes for the development of the human urinary system and eye 1). In utero, it regulates gene expression for the early development of the eye, kidney, ear, brain, and spinal cord, and after birth, it is involved in cellular stress response, apoptosis signaling, and vascular development. It functions by forming multiprotein complexes with other nuclear proteins, and mutations can disrupt this interaction.
PAX2 is a gene that determines the ventral side of the eye and is involved in the closure of the embryonic fissure.
Normal renal mesenchymal differentiation and proliferation are PAX2-dependent, and PAX2 is intensively expressed in the renal tubules and ureteric bud 2). PAX2 positively regulates the expression of the WT1 gene (Wilms tumor suppressor gene) and is involved in mesenchymal-epithelial transition during kidney development 3). Disruption of PAX2 expression leads to renal and ureteral hypoplasia/dysplasia (including cystic changes).
PAX2 expression during embryogenesis shows a dynamic gradient: expression throughout the optic vesicle → restriction to the ventral optic cup and optic stalk → restriction to the margins of the fetal fissure → complete suppression after birth 2).
Optic disc dysplasia results from abnormal angiogenesis and retinochoroidal hypoplasia. It is thought to involve a different mechanism from true coloboma (failure of fetal fissure closure) 2). When the optic disc is excavated to the periphery, cerebrospinal fluid can flow in from the disrupted glial boundary tissue, potentially causing serous retinal detachment.
PAX2 is expressed throughout the central nervous system and activates or suppresses numerous genes in transcriptional networks 4). In mouse models, PAX2 heterozygous knockout shows behavioral changes, microglial reduction, and learning and memory deficits. Associations with neurodevelopmental disorders (autism, developmental delay, mild intellectual disability) have been reported in cohort studies from Japan and China 4).
Wells et al. (2025) reported phenotypes beyond the conventional renal and ocular symptoms in PAX2-related disorders, including acute ataxia, autistic regression (rapid regression of speech and social skills in early childhood), inguinal hernia, and lipodystrophy 4). This case involved a microdeletion that could not be detected by SNP microarray or exome sequencing but was identified for the first time by whole-genome sequencing (using an incomplete penetrance filter), demonstrating the need for systematic documentation of the broader phenotype of PAX2-related disorders.
Nguyen et al. (2021) reported that spontaneously resolving oligohydramnios is an early ultrasound finding of renal coloboma syndrome3). This case demonstrates the importance of family monitoring across two generations and prenatal diagnosis, and prenatal genetic diagnosis using the CAKUT next-generation sequencing panel was useful.
PAX2 mutations have been detected in 6.5% (38 out of 457) of Japanese CAKUT patients, and elucidation of the clinical and genetic diversity of PAX2 mutations is ongoing1). Currently, no gene therapy specifically for PRS has been developed.
Shanmuga Jayanthan S, Senthilkumar S, et al. Renal Coloboma Syndrome—An Autosomal Dominant Genetic Disorder. Indian J Radiol Imaging. 2023;33(1):55-58.
Ng B, De Silva SR, Bindra MS. Papillorenal syndrome: a systemic diagnosis not to be missed on fundoscopy. BMJ Case Rep. 2021;14(7):e243476.
Nguyen A, Nguyen AV, Lipa KL, et al. Resolving severe oligohydramnios as an early prenatal presentation of renal coloboma syndrome. Clin Case Rep. 2021;9(9):e04740.
Wells PA, Basu AP, Yates LM. ‘No causative variants found’: an unusual presentation of PAX2-related disorder. BMJ Case Rep. 2025;18(1):e262455.
