Papillorenal syndrome overview

# Overview
Papillorenal syndrome is an autosomal dominant genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve.
The other name for papillorenal syndrome is Renal-coloboma syndrome. It is a rare disorder that affects the development of kidneys and the eyes. Affected kidneys are usually small or underdeveloped and may progress to ESRD when the kidneys are no longer able to filter the fluids. One or both the kidneys can be involved In the eyes, various malformations noted are malformed optic nerve and occasionally a hole in the retina known as coloboma. Some of the affected individuals may experience vision loss. Hence the name is given as Renal-coloboma syndrome. Other less common symptoms associated with the disease include vesicoureteral reflux, loose abnormal joints, numerous kidney cysts, and minimal hearing loss.

# Historical Perspective
Papillorenal syndrome for which another term is Renal-coloboma syndrome (RCS). This condition usually consisting of renal anomalies plus optic nerve dysplasia. It is transmitted to future generations in an Autosomal dominant fashion. First clearly described by Weaver al in 1988. In two brothers having ESRD with coloboma in the eyes. In 1995, the association of dominant mutations in the PAX2 gene with RCS was made. It was studied in a two-generation family having renal dysplasia, coloboma of the optic nerve, and also the presence of vesicoureteral reflux. There are different opinions regarding the name of this condition between the observers. Papillorenal syndrome is a combination of renal and ocular anomalies. Eccles and Schimmenti, 1999; Negrisolo et al., 2011 summarized Less common findings associated with the expression of the PAX2 gene in numerous tissues with the disease include hearing loss, CNS anomalies, joint problems, ligament laxity, soft skin.

# Pathophysiology
The known cause of the Papillorenal syndrome is mutation of a copy of the PAX2 gene, a gene which is important in the development of both the eye and the kidney. However, approximately half of patients with Papillorenal syndrome do not have defects in the Pax2. This suggests that other genes play a role in the development of the syndrome, though few downstream effectors of Pax2 have been identified.

# Papillorenal syndrome differential diagnosis
The renal coloboma syndrome differentials include most of the disease with renal and ocular anomalies. The numerous important differentials are
- CHARGE Syndrome that includes characteristic five features of the disease including Coloboma, Heart Abnormalities, Choanal Atresia, Growth and development Retardation, Genital Anomalies, Ear and hearing abnormalities. A lot of patients studied under Renal-coloboma syndrome do not have any sort of craniofacial anomalies that are typical of CHARGE Syndrome.
- Branchio-oto-renal syndrome- Renal hypoplasia in these patients makes this an important differential. Pt with PAX6 Mutations - significant overlap with eye findings in patients with PAX6 gene mutation make it an important differential but the renal anomalies that are typical for RCS are absent in these patients.
- COACH Syndrome or Joubert - Important differential due to the presence of both renal abnormalities and coloboma in these patients. However, patients with Renal-coloboma syndrome does not have any developmental abnormality, cerebellar abnormalities, and/or hepatic dysfunction.
- Cat Eye Syndrome - This genetic abnormality is having symptomatic overlap with Renal-coloboma syndrome but the Iris coloboma that is typical for RCS is usually not observed in this disorder.

# Epidemiology and demographics
The Prevalence of the disease and the prevalence at birth is still unknown. In a study conducted in 90 families, they found 177 mutation-positive cases. The number of individuals with mutation-negative is not known in that study. The conclusion derived showed no ethnic predilection for the disease. The major component found in the causation of RCS is PAX2 gene (10q24) in half of the patients with renal and optic nerve abnormalities.

# Risk Factors
The pathophysiology and the risk factors responsible for the development of Renal-coloboma syndrome is mainly genetic and related to the expression of PAX 2 gene. So the genetic inheritance is the main risk factor or the important determinant in the causation of Renal-coloboma syndrome. This genetic syndrome keeps on clustering in the future generations.
The environmental risk factors that impact the pregnancy like alcohol and some drugs may also contribute to the development of Renal-coloboma syndrome. In conclusion, RCS leads to the abnormal development of organs like kidney and eyes during the pregnancy period. The abnormal development of eyes usually happens in the third trimester during that time the eyes are formed. The abnormalities usually occur due to the impairment in the closure of the optic disc. It usually depends on which specific part or areas of optic fissure fails to close.

# Natural History, Complications and prognosis
RCS is an autosomal dominant disorder characterized by renal and ocular anomalies. It is mainly relate to the PAX2 gene mutations. Epidemiological estimated incidence of coloboma is about 1 in 10,000 births. Only the coloboma itself is estimated to account for 3-11% of blindness in children's worldwide. Prevalence of disease is still unknown with more than 60 cases are reported in the scientific literature. The most common complications associated are: End stage renal disease, VUR (Vesicoureteral reflux), Eyelid coloboma, Iris coloboma. The prognosis for renal coloboma syndrome depends primarily on the treatment the patient is receiving. The prognosis for renal coloboma syndrome is worse in the presence of congenital anomalies in the patient.

# Diagnosis

## History and Symptoms
The Ocular and renal anomalies are the most important diagnostic findings representing in patients with characteristic signs and symptoms. Mutation in PAX2 Gene causes optic disc dysplasia and coloboma seen in most of the cases is due to the failure of the choroidal fissure to close. Despite the similarities with coloboma and morning glory anomaly, significant differences exist such that optic disc dysplasia cannot be classified as either one entity. Optic disc dysplasia is noted by an ill-defined inferior excavation, the convoluted origin of the superior retinal vessels, an excessive number of vessels, Infrapapillary pigmentary disturbance, and slight band of retinal elevation adjacent to the disk. Some patients have the normal or near-normal vision, but others have visual impairment associated with the disease, though it is not certain if this is due only to the dysplastic optic nerves, or a possible contribution from macular and retinal malformations. The most common malformation in patients with the syndrome is kidney hypoplasia, which is small and underdeveloped kidneys, often leading to end-stage renal disease (ESRD). Estimates show approximately 10% of children with hypoplastic kidneys are linked to the disease. Many different histological abnormalities have been noted, including a decrease in nephron number associated with hypertrophy, focal segmental glomerulosclerosis, interstitial fibrosis, and tubular atrophy, Multicystic dysplastic kidney.

## Physical Examination
In most of the patients, the symptoms will differ depending upon a case by case basis. People with a similar disease might have a variable presentation and may not have all the mentioned symptoms. This valuable information is usually collected from the database of Human phenotype Ontology (HPO). The HPO usually collects the symptoms is usually described or mentioned in the various publications and medical resources. The most common manifestations are Enlargement of the optic disc with blood vessels seen coming out from the periphery. Retinal vessels observed in patients with Renal-coloboma syndrome are more in number and tortuosity as compared to see in normal individuals. Less commonly seen anomalies are Scleral staphyloma, Optic nerve cyst, Microphthalmia, Reduced corneal diameters, Foveal hypoplasia, and macular anomalies. The most common renal abnormalities are Renal hypoplasia/ hypo dysplasia kidneys that have a malformed function with a small number of functional glomeruli and can develop ESRD at any point in the disease. Somewhere around 10% of the patients with these kidneys found to have PAX2 gene mutation. Oligomeganephronia Condition seen in some of the patients with Renal-coloboma syndrome and this usually refers to the marked reduction in the number of functionally intact nephrons Compensatory glomerular hypertrophy seen. Glomerulosclerosis and meningeal fibrous deposits are the most common findings seen on histopathology. Multicystic dysplastic kidneys- These are commonly seen in around 10% of the patients reported with RCS. ESRD- End-stage renal disease can happen anytime during the course of the disease.
Lab Findings
The diagnosis of Renal coloboma syndrome is mainly limited to renal and optical anomalies along with the presence of PAX2 gene mutation. So there is not many roles studied in terms of lab findings except doing the genetic workup for PAX2 Gene mutation. Some rare and variant cases of PAX2 gene may also have the Renal histological findings similar to FSGS and that can be further studied and explored in lab conditions.
Other diagnostic studies
The exact criteria for Renal-coloboma syndrome have not been established so far however by seeing the patients clinically the findings of optic nerve coloboma and hypo dysplasia of kidneys are the characteristic abnormalities seen in patients with Renal coloboma syndrome. and out of that nearly half of the patients have a mutation in PAX2 Gene. It was first observed and concluded by Bower and Schimmenti.

# Medical Management
The medical management for the patients suffering from Renal-coloboma syndrome consists of a combination of preventive as well as a curative component for the complications or the clinical manifestations happening in patients clinically. The most important component is the clinical evaluation of patient symptoms and signs. The most common evaluation involves a careful assessment of Renal and optical manifestations. The early evaluation and workup should be done in patients to cover up all the possible aspects of clinical manifestations. The prevention of secondary complications is usually important in patients with Renal-coloboma syndrome. The ongoing treatment for hypertension or any other medical illness should be provided to the patients that will further help in the prevention of the development of End-stage renal disease. Evaluation of family members is also important and must be done to detect any asymptomatic individual in the family so he can be managed at the earliest possible time and severe complications in those patients can be avoided.