Ferit Kulali  ( Dr. Behcet Uz Child Disease and Pediatric Surgery Training and Research Hospital, Turkey )
Ahmet Yagmur Bas  ( Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Turkey )
Fatma Iyigun Guzel  ( Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Turkey )
Husniye Yucel  ( Dr. Sami Ulus Maternity and Children Research and Training Hospital, Turkey )
Caner Kara  ( Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Turkey )
Cigdem Uner  ( Dr. Sami Ulus Maternity and Children Research and Training Hospital, Turkey )
Nihal Demirel  ( Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Turkey )

Papillorenal syndrome, also known as renal coloboma syndrome, is characterised by congenital optic disc anomalies and renal abnormalities. Mutations in the PAX2 gene, which plays a critical role in embryogenesis, cause this syndrome. Other related anomalies are less commonly observed.

To our knowledge, this is the first case reported in the literature in which Papillorenal syndrome accompanied various dysmorphic features.

Keywords: Renal coloboma syndrome; PAX2-related disorder; coloboma of optic nerve, multicystic dysplastic kidney; eye abnormalities.

DOI: https://doi.org/10.47391/JPMA.1158

 

Introduction

 

Papillorenal syndrome, also known as renal coloboma syndrome, is characterised by congenital optic disc anomalies and renal abnormalities.¹ Since the first case was reported by Rieger, more than 180 cases with Papillorenal syndrome have been reported worldwide.² This syndrome is inherited in an autosomal dominant pattern and often associated with mutations in the PAX2 gene. The PAX2 gene is located on chromosome 10 that is expressed in primitive cells of the kidney, ureter, eye, ear and central nervous system.³ A diagnosis of Papillorenal syndrome should be made in the presence of characteristic fundus findings and renal disease.² Other extrarenal manifestations such as Arnold-Chiari malformation, seizures, and joint laxity have been observed in less than 20% of Papillorenal syndrome patients.⁴

We believe, we are reporting the first case of minor dysmorphic features accompanied with Papillorenal syndrome.

 

Case Report

 

A girl was born by Caesarean section at 35 weeks gestation, weighing 1,400 gr, with head circumference of 28.0 cm, to non-consanguineous parents. The case was seen at Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital in June 2016. The mother was a 33-year-old gravida 2 para 2 and had received regular prenatal care throughout the pregnancy. Family history was unremarkable. A third-trimester ultrasound showed intrauterine growth restriction and multiple cortical cysts within the left kidney. Amniocentesis was performed for elevated maternal alpha-fetoprotein level and the karyotype was 46, XX.

There were no complications during delivery, and Apgar scores were 7 and 8 at one and five minutes, respectively. After birth, the infant was noted to have mild respiratory distress. She was started on oxygen supplementation and was transferred to the neonatal intensive care unit. Physical examination revealed respiratory rate of 66 breaths per minute, dysmorphic features including hypoplastic nails, clinodactyly of the second fingers and toes, equinovarus deformity in left foot, together with hypotonia. Laboratory tests were within normal limits. Chest radiography and cranial ultrasound were normal. Abdominal ultrasound scan showed left multicystic dysplastic kidney and right hydronephrosis grade 1 (Figure-1).

Echocardiography revealed patent foramen ovale. Ophthalmological examination showed “morning glory” of right optic disc (Figure-2).

On the basis of the ophthalmological findings along with abdominal ultrasound scan, Papillorenal syndrome was diagnosed. Renal function and urine test results, blood pressure measurements, and auditory tests (auditory evoked potentials, otoacoustic emissions) were within normal limits. All family members were examined for ocular and renal findings but there were no signs of kidney or eye disease. She was discharged from the hospital on postnatal day 33. The patient was given antibiotic prophylaxis for prevention of urinary tract infection and was regularly followed by a multidisciplinary team including a neonatologist, a paediatric nephrologist, an audiologist, a paediatric genetic specialist and a paediatric ophthalmologist. Physical, neurological and developmental assessments were performed for 18 months but no complications were noticed in the patient. The parents were concerned about the long-term prognosis of Papillorenal syndrome including the risk of development of end stage renal disease and visual outcome.

 

Discussion

 

Papillorenal syndrome is characterised by congenital optic disc anomalies and renal abnormalities. We suspected that PAPRS due to ocular and renal findings. The characteristic optic disc anomalies are optic nerve dysplasia, optic disc coloboma and morning glory anomaly (a congenital cavity of the peripapillary fundus, expansion of the optic disc). The most common renal findings are renal hypoplasia, renal hypodysplasia, vesicoureteric reflux, oligomeganephronia, horseshoe kidney and multicystic dysplastic kidney.¹ In our patient, there are both the morning glory anomaly and multicystic dysplastic kidney. Diagnosis of the Papillorenal syndrome is typically made on the basis of clinical findings. It has been reported that the majority of published cases have mutations in PAX2.¹ In our patient, chromosomal analysis revealed 46,XX with deletion of chromosome 10 (q25.2q26.3). Sanger sequence analysis of the PAX2 gene is important as there is a relationship between the presence of PAX2 gene mutations and the risk of developing end-stage kidney disease, but we could not achieve this due to financial problems. In some reports, optic disc appearance is considered a more reliable finding than PAX-2 gene mutation for diagnosis.⁵ The diagnosis of Papillorenal syndrome is made in the presence of chromosomal 10 (q25.2q26.3) deletion, morning glory anomaly and multicystic dysplastic kidney.

Papillorenal syndrome can also be associated with other anomalies as Arnold-Chiari malformation, seizures of unknown cause, sensorineural hearing loss, and joint laxity.⁴ To our knowledge, skeletal abnormalities associated with Papillorenal syndrome have not yet been described. We report various abnormalities including hypoplastic nails, clinodactyly, equinovarus deformity, and hypotonia. Diagnosis of Papillorenal syndrome was made by Hoefele et al⁴ and the same mutations on chromosome 10q were also reported. Although our patient had hypoplastic nails, clinodactyly, equinovarus deformity, and hypotonia, their patient had only pes calcaneous. These results indicate that the mutations probably cause dysmorphic features in patients with Papillorenal syndrome. Minor dysmorphic features may occur due to deletions in chromosome 10q.

The differential diagnosis of Papillorenal syndrome should include CHARGE syndrome, branchio-oto-renal syndrome and Joubert syndrome.² Comprehensive evaluation is essential, particularly before development of complications to assess disease extent and severity. No accurate and reliable prognostic data for Papillorenal syndrome is available due to rarity of the syndrome. While it increases the risk of retinal detachment in patients with optic nerve dysplasia (coloboma), patients with mutations in PAX2 have an increased risk of developing end-stage renal disease. Visual acuity ranges from normal to light perception only. Impaired visual acuity have been reported in approximately 75% of Papillorenal syndrome patients.² Renal disease can occur at any age from birth to 79 years and usually is progressive.² Early identification of patients with Papillorenal syndrome is important because future complications such as blindness, end-stage renal disease and hearing loss can be followed through.

 

Conclusion

 

Papillorenal syndrome, also known as renal coloboma syndrome, is a rare clinical, radiologic and ophthalmological condition. Papillorenal syndrome should be considered in the presence of the combination of renal and ocular anomalies. The patient with papillorenal syndrome should be monitored closely due to high-frequency sensorineural hearing loss as well as ocular and renal anomalies.

In conclusion, we have presented one patient with a classic clinical presentation of Papillorenal syndrome having skeletal abnormalities not previously described.

 

Informed Consent: Written informed consent was obtained from the parent of the patient who participated in this study.

Disclaimer: None.

Conflict of Interest: None.

Financial Support: None.

 

References

 

1.      Schimmenti LA. Renal coloboma syndrome. Eur J Hum Genet 2011;19:1207-12. doi: 10.1038/ejhg.2011.102.

2.      Bower MA, Schimmenti LA, Eccles MR. PAX2-Related Disorder. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al, eds. GeneReviews® Seattle, WA: University of Washington, Seattle; 1993–2021.

3.      Eccles MR, Schimmenti LA. Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations. Clin Genet 1999;56:1-9. doi: 10.1034/j.1399-0004.1999.560101.x.

4.      Hoefele J, Gabert M, Heinrich U, Benz K, Rompel O, Rost I, et al. A novel interstitial deletion of 10q24.2q24.32 in a patient with renal coloboma syndrome. Eur J Med Genet 2012;55:211-5. doi: 10.1016/j.ejmg.2012.01.011.

5.      Khan AO, Nowilaty SR. Early diagnosis of the papillorenal syndrome by optic disc morphology. J Neuroophthalmol 2005;25:209-11. doi: 10.1097/01.wno.0000177303.67715.74.