A novel PAX2heterozygous mutation in a family with Papillorenal syndrome: A case report and review of the literature



Papillorenal syndrome (PAPRS) is a rare inherited disorder often involves abnormalities of eye and kidney. Paired box 2 ( PAX2 ) gene, which is widely expressed in the development of the organs including kidney, ureter, eye, ear, and central nervous system has been considered an underlying cause of PAPRS. The present work aims to further our understanding of PAX2 gene and PAPRS by reporting a family with PAPRS associated with a novel PAX2 mutation and describing ocular manifestation of PAX2 mutation in previous literatures.


We herein present a family with PAPRS presented with typical congenital optic disc defects and mild renal dysplasia. Through screening of candidate genes based on the next-generation sequencing, the heterozygous PAX2 mutation c.175C > T (p. Arg59Trp) was identified which had never been reported.


The study expands the genetic and clinic spectrum of PAPRS. Further review of detailed ocular manifestation and genotypes of PAX2 mutation in previous study improves the recognition of the ocular phenotypes’ spectrum, assists in the identification of PAPRS. Moreover, this study reveals that PAPRS is a systemic disorder with heterogeneous diverse phenotypes, and shows the importance of gene panel sequencing in the diagnosis of PAPRS which could achieve high diagnostic rates.


Papillorenal syndrome (PAPRS; MIM 120330), also known as renal-coloboma syndrome is a rare autosomal dominant disease characterized by abnormal optic nerve and renal findings. In 1977, PAPRS was first described in a family with diverse manifestations of eye and kidney by Rieger. According to previous studies, commonly observed ocular manifestations of PAPRS are various, including optic nerve coloboma, morning glory anomaly, and excavation of the optic disc. Other infrequent findings may include keratopathy, scleral staphyloma, optic nerve cyst, microphthalmia, and pigmentary macular dysplasia. Kidney disorders like renal hypoplasia, multicystic kidney, oligomeganephronia, and vesicoureteric reflux leading to end-stage renal disease are always represented in patients with PAPRS. About one-half of patients who have findings of optic nerve malformation and renal dysplasia harbor a mutation in the Paired box 2 ( PAX2 ; MIM 167409) gene. PAX2 is a nuclear transcription factor gene abundantly expressed in the kidney, eye, cochlea, pancreas, and central nervous system during embryogenic development. The mutations in PAX2 gene have been recognized as a critical cause of PAPRS.

Here, we present three patients in a family consist of three generations, who was suspected as PAPRS based on their ocular manifestations, though their renal abnormalities are insignificant. The diagnosis was further confirmed by detection of a novel PAX2 heterozygous mutation using the next-generation sequencing.

Case report

Patient 1 ( Fig. 1, II :1), a 46 years old female, was admitted to our hospital because of diminution of vision in the right eye for one year in March 2016. The best corrected visual acuity (BCVA) of her right eye was 0.15 and 0.6 in the left eye. There was no obvious abnormity found in the examination of anterior segment examination, pupillary reflexes, and external ocular eye movements. Fundus examinations ( Fig. 2 A, B) revealed bilateral optic nerve abnormalities with temporal optic disc pit (ODP)——an oval, gray-white depression with absent of central retinal vessels and numerous cilioretinal vessels. Meanwhile the right eye presented with maculopathy including cystic edema and retinal detachment (RD). The spectral domain optic coherence tomography (SD-OCT) (Heidelberg Engineering, Heidelberg, Germany) examination ( Fig. 3 A, C) of the right eye showed temporal ODP, macular cystic edema, retinal detachment and disruption of IS/OS. And temporal ODP, retina fuzzy border, and discontinuity of IS/OS were found in SD-OCT of the left eye ( Fig. 3 B, D). The ultrasound of the right eye also showed retina edema and detachment. The systemic evaluation was unremarkable. In previous medical history, the patient underwent right mastofibroma resection six years ago and hysteromyomectomy four years ago. The diagnosis of the patient was amblyopia, bilateral ODP, cystoid macular edema and serous retinal detachment of right eye. Then, the patient was treated with a pars plana vitrectomy (PPV), internal limiting membrane (ILM) peeling, and fluid-gas exchange with C3F8 in the right eye. As shown in Fig. 3 , the RD and macular edema were completely recovered in two years with an improved BCVA (OD 0.3 OS 0.8).

Fig. 1

The pedigree of the family in this study.

Fig. 2

Fundus images of the patients.

(A, B) Fundus image of patient 1 showing the abnormal appearance of bilateral optic discs with temporal optic disc pit (ODP). The absence of central retinal vessels and numerous cilioretinal vessels.

(C, D) Fundus image of patient 2 showing the presence of optic disc central excavation and chorioretinal atrophic lesion in both eyes, more prominent in left eye(D).

(E, F) Fundus image of patient 3. A typical optic nerve coloboma in the left eye could be observed (F).

Fig. 3

SD-OCT images of the patients.

(A, C) SD-OCT images in the right eye of patient 1 showing severe retinoschisis in the whole macular area which termed to ODP maculopathy and evident neurosensory detachment.

(B, D) A temporal ODP, retina fuzzy border, and discontinuity of IS/OS are presenting in SD-OCT in the left eye of patient 1.

(E) The macular cystic edema had significant improvement but neurosensory detachment remained in the right eye of patient 1 in one year after surgery.

(F) The RD and macular edema were completely recovered in the right eye of patient 1 in 2 years after surgery.

(G) SD-OCT images of the patient 2 showing a macular hole in the left eye.

(H) SD-OCT images of the patient 3 showing the optic nerve coloboma in the left eye.

Of note, her mother ( Fig. 1, I :1) also suffered from ocular disease. In July 2010, patient 2 ( Fig. 1, I :1), a 67 years old female, who complained about floater accompanied by blurred vision of left eye for one year was admitted to our hospital. The BCVA was 0.4 of her right eye and HM/BE of the left eye. Under fundus examination, as shown in Fig. 2 , the left eye showed retinal proliferative membrane, RD with obviously elevated retina, and abnormal appearance of the optic disc with a central excavation and chorioretinal atrophy. The Optic disc central excavation and chorioretinal atrophic lesion were also noted in the right eye but much milder. The SD-OCT revealed a macular hole (MH) in the left eye ( Fig. 3 ). She had a history of high myopia for 30 years. Previously she underwent a surgery of phacoemulsification with intraocular lens (IOL) implantation in the left eye for cataract in 2008. She was treated with PPV, photocoagulation, and silicone oil injection in the left eye during hospitalization. Seven months later, the silicone oil was removed. In the last follow-up visit, the OCT scan showed the macular hole of the left eye did not fully recover but remained stable and BCVA achieved a slight improvement (OD 0.5 OS FC/BE).

Patient 3 ( Fig. 1, III :1), the daughter of patient 1, was born in 1998. She was diagnosed as strabismus shortly after birth. The strabismus surgery and amblyopia training were performed in the left eye when she was six years old while no other medical history of interest. The ophthalmologic examination revealed the congenital abnormality of her left optic nerve presented with optic nerve coloboma——a bowl-shaped inferior excavation with enlarged optic nerve head ( Fig. 2 E, F). Up to now, she was under close follow-up and remained a stable vision——BCVA of right eye is 1.0 with −1.00D myopic correction and 0.9 of left eye with −6.25D myopic correction without any complication.

We assumed the existence of a hereditary cause associated with optic disc abnormality among this family. After obtaining informed consent, the genomic DNA from affected patients (patient 1–3) in this family was extracted from peripheral blood according to standard procedures. Mutations were screened among 792 candidate genes using the custom-designed Target_Eye_792_V2 chip (BGI-Shenzhen, China). The detailed procedure was described previously. The genetic study revealed that all three patients carried the heterozygous PAX2 mutation c.175C > T (p. Arg59Trp), consisting of a nucleotide exchange from C to G at position 175 in exon 2 of PAX2 gene, leading to a substitution of the arginine to tyrosine at position 59 of the protein (p. Arg59Trp). The missense alteration was predicted a pathogenic effect by all four software (SIFT/LRT/Mutation Taster/FATHMM). To the best of our knowledge, this variant has not been previously reported in the literature.

To further evaluate the condition of the patients, routine urinalysis, kidney functions, and abdominal ultrasound scans were performed, even though none of them complained of symptoms associated with renal disorders. As shown in Table 1 , there were no renal abnormality except for patient 2 presented with multiple renal cysts and patient 3 had mild elevated BUN (8.9mmol/L, normal range: 2.5–6.4 mmol/L).

Jul 10, 2021 | Posted by in OPHTHALMOLOGY | Comments Off on A novel PAX2heterozygous mutation in a family with Papillorenal syndrome: A case report and review of the literature

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