Papillorenal Syndrome

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Article initiated by:

Andrew Go Lee, MD, Chaow Charoenkijkajorn, M.D., Grace Kuang

All contributors:

Andrew Go Lee, MD, Chaow Charoenkijkajorn, M.D., Mohammad Pakravan, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS, Nagham Al-Zubidi, MD, Ayman Okla Suleiman, MD, Chaow Charoenkijkajorn, M.D.

Assigned editor:

Ayman Okla Suleiman, MD

Review:

Assigned status Up to Date

 by Ayman Okla Suleiman, MD on March 28, 2024.

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Disease Entity

Papillorenal Syndrome (PRS)

Disease

Papillorenal Syndrome (PRS) is a congenital autosomal dominant inherited disorder that impacts kidney and eye development. Although phenotypic manifestations vary amongst individuals, typical characteristics of PRS include renal hypoplasia and optic nerve dysplasia. Other possible malformations of PRS include abnormalities in the auditory, musculoskeletal, dermis, and central nervous system (CNS). The involvement of organ systems is more commonly bilateral but can also be unilateral. Renal underdevelopment often leads to end stage renal disease while eye malformations can potentially lead to retinal detachment and blindness. PRS is also referred as renal coloboma syndrome (RCS), PAX2-related disorder, optic nerve coloboma with renal disease, coloboma-ureteral-renal syndrome, and optic coloboma, vesicoureteral reflux, and renal anomalies syndrome.

Etiology

Approximately half of patients with PRS have a mutation in the paired-box PAX2 gene located on chromosome 10q24. In utero, this gene is necessary for making a protein transcription factor involved in altering gene expression for the early development of the eyes, kidneys, ears, brain, and spinal cord. Following birth, the PAX2 protein continues to have important cellular functions in mediating cellular stress responses, apoptosis signaling processes, and vascular development.

Like other transcription factors, the PAX2 protein first interacts with other nuclear proteins and forms a multi-protein complex in order to perform its function. PAX2 gene mutations in PRS cause either haploinsufficiency from complete loss of protein function in one allele, or a missense mutation that leads to partial or abnormal protein function. As a result, the faulty protein product is unable to interact with its multi-protein complex and therefore unable to exert its downstream effects.

Identified mutations are found to be inherited in a heterozygous autosomal dominant fashion as homozygous genotypes are perinatal lethal. However, approximately 65% of patients with both the syndrome and PAX2 mutations do not have a family history. This observation suggests that the PAX2-related syndrome can also be produced from de novo mutations or parental germline mosaicism.

It is also important to note that the presence of a PAX2 mutation is not unique to PRS as the mutation can also be identified in renal diseases separate from the syndrome. PAX2 mutations are found in 8% of individuals with nonsyndromic renal hypodysplasia and 4% of individuals with isolated familial focal segmental glomerulosclerosis. The inverse is also true: papillorenal syndrome does not necessitate an underlying PAX2 mutation. The observation that half of affected individuals do not possess a PAX2 mutation suggests that PRS is a polygenic disorder and other unidentified genes likely contribute to its development. This variety of manifestations and etiologies is reflected in the naming of this collection of findings as a syndrome rather than disease.

Epidemiology

The precise prevalence for PRS is unknown2 with 268 affected individuals recorded in The Human Variome Project PAX2 database to date. No racial or ethnic predisposition for the syndrome has been found. Studies have approximated that 10% of children with unilateral or bilateral renal hypoplasia will have point mutations in the PAX2 gene linked to PRS.

Risk factors

A de novo or inherited PAX2 mutation would constitute the greatest risk factor for development of PRS. Additionally, the presence of teratogens during pregnancy can increase risk for multi-organ malformations. This is especially true for teratogen exposure during the embryonic period, postfertilization weeks 3 to 8, during which most organs including the kidney and eye develop.

Risk factors associated with increased complications and worse prognosis include systemic diseases that compromise kidney or eye structures and functions (i.e. hypertension, hypercholesterolemia, hyperglycemia, etc.). These systemic factors would promote blood vessel remodeling and increase risk for vascular dysgenesis.

General Pathology

Kidney hypodysplasia often leads to early and severe impairment of kidney function. Patients commonly develop end-stage renal disease (ESRD) and require early dialysis and/or renal transplant in young adulthood. One study reported an average age of diagnosis of ESRD at 19.5 years old, but the range of ages is highly variable. Commonly, patients also have associated vesicoureteral reflux. Other presentations of renal malformations include glomerular disease, tubular disease, interstitial disease, and multiple renal cysts.

While renal underdevelopment often leads to ESRD, eye malformations present across a spectrum of severities. 75% of individuals report some degree of visual acuity impairment. Mild presentations feature retinal vessels that exit from the periphery, instead of the center, of the optic disc without disturbance of the structure of the disc itself. Mild optic disc dysplasia is often associated with normal visual acuity. Severe presentations can include optic nerve colobomas and deep excavation of the optic nerve akin to morning glory disc anomaly, which are often associated with poor visual acuity and light perception only. Other presentations of ocular malformations include microphthalmia, anomalous uveal perfusion, central retinal artery hypoplasia, scleral staphyloma, lens malformations, retinal colobomas, macular and foveal malformations, optic nerve pits, and optic nerve cysts. Notably, iris colobomas are not associated with the syndrome.

Approximately 92% of individuals with PRS have renal abnormalities and 72% of individuals have optic nerve abnormalities.2 Extrarenal and extraocular features are less common in PRS but include high-frequency sensorineural hearing loss, CNS malformations, joint and ligament laxity, soft skin, and endocrinological abnormalities. However, definitive connections to the syndrome have not yet been established for these additional presentations.

Diagnosis

Symptoms

Renal dysfunction is often the earliest sign of PRS due to its early presentation, higher prevalence, and greater severity of disease. It is rare for renal abnormalities to remain clinically silent and go unnoticed. Kidney hypodysplasia can begin to cause clinical symptoms in utero due to oligohydramnios and resultant Potter sequence. In adults, chronic renal failure can present with recurrent nephrolithiasis, pyelonephritis, electrolyte abnormalities, and fluid retention.

In contrast, ocular symptoms in PRS can vary from normal vision to significant visual impairment depending on size and location of malformation. Mild structural changes may not present with any functional impairments and remain undiagnosed. Careful examination and recognition of characteristic ocular findings can lead to earlier diagnosis and management of PRS, potentially slowing the progression of renal dysfunction and complications.

Physical examination

Optic disc dysplasia is considered the most consistent and reliable finding, even more so than genetic analysis of known mutations. Disc excavations are typically central with peripherally exiting tortuous retinal vessels and thinning of the peripheral retina. Renal histopathology can demonstrate decreased number of functional nephrons and glomeruli, glomerulosclerosis, tissue disorganization, as well as multiple cysts.

Diagnostic procedures

Molecular genetic sequence testing can identify a heterozygous PAX2 gene mutation present in approximately half of individuals with PRS. As this mutation is observed to exhibit an autosomal dominant inheritance pattern, the patient’s relatives and potential partners may choose to be tested and seek genetic counseling. Preimplantation genetic diagnosis and prenatal testing of a fetus via molecular genetic testing or clinical ultrasounds should also be considered in a parent with PRS.

In individuals with no known mutation, dilated ophthalmologic exam and renal workup may be useful in elucidating a diagnosis. It is important to note that if a characteristic syndromic finding is identified on examination of the kidney or eye, the patient should be referred for investigation of the other organ system as well.

Differential diagnosis

Other disorders that feature both kidney and eye involvement include CHARGE syndrome (C-coloboma, H-heart defects, A-atresia choanae, R- retardation of growth, G-genital and urinary abnormalities, and E-ear abnormalities), branchio-oto-renal syndrome, acro-renal-ocular syndrome (AROS), and COACH syndrome (C-cerebellar vermis defect as in Joubert syndrome, O–oligophrenia, A–ataxia, C–coloboma, H-hepatic fibrosis).

Optic disc coloboma is also associated with focal dermal hypoplasia, linear sebaceous nevus syndrome, Walker-Warburg syndrome, Aicardi syndrome, Goldenhar syndrome, and Noonan syndrome. Morning glory anomaly, congenital glaucoma, and normal-tension glaucoma are also considered when presented with optic nerve excavation and retinal vessel dysplasia in a young patient. Holistic consideration of patient history and clinical presentation are necessary in the evaluation of PRS.

Management

Course and Treatment

There is currently no medications or gene therapies directed in the treatment of PRS. The main therapeutic goals are prevention and management of associated complications.

Close management of risk factors such as hypertension and vesicoureteral reflux is important in delaying or preventing chronic renal failure. Following onset of ESRD, dialysis and/or renal transplant would be important treatment modalities to consider.

Retinal detachment and blindness can be prevented through protective lenses. Following onset of significant visual impairment, low vision aids can be utilized to improve accessibility and functionality.

As syndromic presentations span multiple organ systems, clinical care should as well. The care team would ideally comprise of ophthalmology, nephrology, audiology, and genetics. Close follow-up with an ophthalmologist and nephrologist is important to trend progression of syndrome as well as initiate prompt treatment of complications as necessary. Regular audiometric evaluations are also recommended for monitoring of sensorineural hearing ability.

Prognosis

The prognosis of PRS is largely dependent on the extent of involvement of the various organ systems as well as presence of concomitant conditions increasing risk for complications. For the eye specifically, degree of visual impairment is influenced by size and location of anomalies (i.e. deep excavation of optic disc is associated with poor visual prognosis). Overall, prognosis is generally worse in individuals with early development of complications.

Summary

PRS is a congenital autosomal dominant disorder producing renal hypoplasia and optic nerve dysplasia. In addition, PRS may affect the auditory, musculoskeletal, dermis, and CNS. End stage renal disease is common and chronic ocular disease may lead to retinal detachment and blindness. A multidisciplinary approach is recommended for PRS.

Additional Resources

• Porter D, Vemulakonda GA. Blood Pressure. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/anatomy/blood-pressure-list. Accessed January 06, 2023.