Keywords
optic nerve dysplasia - papillorenal syndrome - renal coloboma syndrome
Introduction
Renal coloboma syndrome (RCS) also known as papillorenal syndrome describes a condition
consisting of optic nerve dysplasia and renal malformations. The inheritance pattern
is autosomal dominant. The first description of RCS was made by Weaver et al in 1988
in two brothers who had end-stage kidney disease (ESKD) with interstitial nephritis
and optic nerve colobomas.[1] Later in 1995, autosomal dominant mutations in the transcriptional regulator, paired
box 2(PAX2), were identified in the family.[2] Apart from optic nerve coloboma, other associated ocular findings may include a
small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst, and
pigmentary macular dysplasia.[3] Apart from hypodysplastic kidneys, other associated renal anomalies include multicystic
dysplastic kidney and horseshoe kidney.[4] Here, we present a case of 16-year-old male with complaints of right eye blindness
and renal failure.
Case Report
A 16-year-old male patient presented with complaints of bilateral periorbital swelling
and decreased urine output since 2 months. The patient also had complaints of loss
of vision in the right eye since 6 years, evaluated and diagnosed with optic disk
coloboma extending to the optic nerve (right > left). There was no family history
of similar problems and renal dysfunction. On examination, the patient had pallor.
Blood pressure, pulse, respiratory rate, and oxygen saturation were within normal
limits.
Laboratory investigations revealed elevated serum creatinine (15.5 mg/dL) and blood
urea (223 mg/dL) suggestive of renal failure, and reduced hemoglobin (5.0 g/dL), normal
serum iron (77 µg/dL), elevated total iron binding capacity (206 mg/dL), and elevated
serum ferritin (1276 ng/dL) suggestive of anemia of chronic disease.
B-mode ultrasound of the abdomen was done which revealed bilateral contracted kidneys
(right measures 5.8 × 3.0 cm and left measures 5.5 × 3.2 cm) with renal parenchymal
echogenicity equal to that of renal sinuses suggestive of bilateral grade 3 renal
parenchymal changes ([Fig. 1A and B]).
Fig. 1 (A and B) B-mode ultrasound shows contracted right and left kidney with renal cortical echoes
equal to that of renal sinuses.
B-mode ultrasound of both orbits ([Fig. 2]) revealed the defect in the posterior aspect of the globe at the level of insertion
of the optic disk head showing herniation of vitreous with a defect measuring 0.67 cm
in width and 0.78 cm in depth on the right side and 0.57 cm in width and 0.31 cm in
depth on the left side.
Fig. 2 Ultrasound of both orbits revealed defect in the posterior aspect of globes at the
level of insertion of optic disk.
Magnetic resonance imaging (MRI) of orbits revealed a smaller size of the right globe
with a focal posterior defect at the level of optic disk forming a retrobulbar fluid
cyst with vitreous herniation within. A focal posterior defect at the level of optic
disk was also noted on the left side. MRI brain revealed no associated midline or
skull base anomalies ([Figs. 3] and [4]).
Optical coherence tomography of orbit revealed retinochoroidoscleral excavation with
a fine layer of retina covering the sclera with cystoid edema temporal to optic disk
coloboma.
Based on the clinical features, laboratory investigations, and imaging findings, the
patient was diagnosed to be a case of renal coloboma syndrome with end-stage renal
disease. Attendees were informed about genetic testing, but since it would not change
the medical management and due to financial constraints, testing was denied. The patient
parents were counseled about the need for a renal transplant in view of the need for
long-term hemodialysis.
Discussion
RCS is an autosomal dominant disorder which shows wide inter- and intrafamilial variability.
It is characterized primarily by ocular signs (77%) and renal manifestations (92%).
The renal features are part of a spectrum of malformations termed congenital anomalies
of the kidney and urinary tract (CAKUT).[5] To date, PAX2 mutations have been the only identified genetic cause associated with RCS.
PAX2 gene, located on chromosome 10q24, is a member of paired box transcription factor
family and is one of the most critical genes involved in the human urinary system
and eye development.[6]
[7] One study showed that 10% (2 out of 20) of patients with urinary tract malformation
who underwent kidney transplantation possessed the PAX2 mutation.[5] Another study in Japan concluded that 6.5% (38 out of 457) of patients with CAKUT
carried the PAX2 mutation.[6] Since the renal disease is identified in 92% of mutated individuals, and eye disease
in 77% of individuals implies that the disorder is highly penetrant.[8]
The most common renal manifestation is renal hypodysplasia, which is usually bilateral
and presented in 65% of involved individuals.[9] Other renal abnormalities include renal insufficiency, cystic kidney disease, vesicoureteral
reflux (VUR), and other CAKUT. Histologically, the kidneys show less than a normal
number of glomeruli with glomerular hypertrophy indicative of oligomeganephronia.[10] Eye abnormalities include optic nerve dysplasia and coloboma, which comprise around
72% of patients, and other findings include retinal coloboma, optic nerve cyst, macular
abnormalities, or lens abnormalities.[8] Consequences of the renal hypodysplasia include hypertension, proteinuria, and renal
insufficiency that frequently progresses to ESKD. Consequences of the ocular malformations
include decreased visual acuity, blindness, and retinal detachment. Reported nonrenal
and nonophthalmological manifestations include high-frequency sensorineural hearing
loss (7%), short stature, developmental delay, autism, CNS malformations (e.g., Chiari
I malformation), hyperuricemia, soft skin, joint laxity, elevated pancreatic amylase,
and short digits.[11] The correct genetic diagnosis is crucial for guiding clinical management and genetic
counseling, especially in familial cases.
Management of the disease should be focused on preventing ESKD and vision loss. Strategies
include blood pressure control, treatment of VUR, avoidance of nephrotoxic drugs,
and prevention of retinal detachment. Renal replacement therapy is recommended and
vision experts may provide assistance to adapt to continued vision loss.
Prenatal testing is another possibility for prevention or awareness, and this can
be done through molecular genetic testing. Additionally, preimplantation genetic diagnosis
should be considered for families known to have papillorenal syndrome.
The differential diagnosis for renal coloboma syndrome includes CHARGE syndrome (coloboma,
heart malformations, atresia choanae, retardation of growth and development, genital
anomalies, and ear and hearing abnormalities), craniofacial or cognitive abnormalities
which are typical of CHARGE syndrome are absent. In patients with PAX6 mutations eye findings may overlap, but renal anomalies are lacking. Patients with
Joubert syndrome can have both colobomas and renal dysplasia; however, developmental
disability, cerebellar hypoplasia, and cerebellar dysfunction are absent in RCS.
Fig. 3 Axial T2 SPIR sequence of orbits shows a focal posterior defect at the level of optic
disk forming a retrobulbar fluid cyst with vitreous herniation within noted on the
right side. A focal posterior defect at the level of optic disk also noted on the
left side suggestive of optic disk coloboma.
Fig. 4 Sagittal FFE sequence of brain shows a focal posterior defect at the level of optic
disk forming a retrobulbar fluid cyst with vitreous herniation within noted on the
right side. A focal posterior defect at the level of optic disk also noted on the
left side suggestive of optic disk coloboma.
Fig. 5 (A and B) Optical coherence tomography images in show a fine layer of retina covering the
sclera with cystoid edema.
