Papillorenal syndrome physical examination

Physical examination

Clinical findings of RCS occur primarily in the ocular and renal systems with reported auditory and central nervous system findings in individual cases. Organ specific findings correspond to tissue-specific PAX2 expression during early embryonic development; the eye, the inner ear, the midbrain/hindbrain, the spinal cord and the urogenital system.7, 8, 9, 10, 11 Ocular findings Eye findings reported in RCS have been reported in 85 patients who have mutations in PAX2.9, 12 The characteristic eye findings include an enlarged optic disc with blood vessels that emerge from the periphery of the disc (optic nerve head) rather than the center of the disc (Figure 1). The disc can be deeply excavated and dysplastic with grey gliotic tissue emerging from the center of the disc. The retinal blood vessels are tortuous and increased in number compared with normal. Reported named findings include optic nerve dysplasia, optic disc coloboma and morning glory anomaly. Associated abnormalities include retinal coloboma, scleral staphyloma, small corneal diameters, optic nerve cyst (Figure 2) and microphthalmia.12, 13, 14 Iris colobomas have not been identified to date in patients with mutations in PAX2.15 Foveal hypoplasia as well as macular abnormalities have been observed.12, 16, 17

Figure 1 Fundus photographs from three patients with renal coloboma syndrome (a–c) and a normal retina for comparison (d). (a) Left retina from a patient with RCS and PAX2 mutation c.76dup.14 The arrow denotes a deeply excavated optic disc. (b) Right retina from a patient with RCS and PAX2 mutation c.76delG.14 The arrow denotes a retinal defect, however, the defect is temporal rather than nasal. (c) Right retina from a patient with PAX2 mutation c.76dup.13 The optic disc is enlarged and excavated. In all three retinae from patients with renal coloboma syndrome the retinal vessels emerge from the edge of the disc rather than the center. (d) A normal retina for comparison. Note that the typical optic nerve is smaller, compact and the retinal vessels emerge from the center of the disc.

Figure 2 MRI of an optic nerve cyst in an affected patient with PAX2 mutation c.76dup denoted by the black arrow.14 Visual acuity ranges from normal to significant visual impairment with blindness. Nystagmus has been documented in a number of reports.3, 12, 16, 18 Anisometropic visual acuity has been reported with some as extreme as 20/20 in one eye and light perception in the other.12 Strabismus has been reported but may or may not be part of the syndrome. Many patients exhibit myopia of various degrees.3, 5, 14, 18 A recent report in a single patient identified calcified keratopathy, possibly secondary to renal failure and posterior lens luxation.19 Other sequelae include retinal detachment. Visual loss may be progressive over time (unpublished) but the mechanism of late onset loss is unknown. Renal findings Renal malformations or insufficiency are identified in nearly all patients with RCS and are frequently identified before the eye malformations.5, 20 Renal findings in individuals with mutations in PAX2 include renal hypoplasia,3 renal hypodysplasia,21 multicystic dysplastic kidney,22 oligomeganephronia23 and horseshoe kidney.24 Renal hypoplasia and hypodysplasia describes small malformed kidneys that have fewer glomeruli that at some point may develop end-stage kidney disease. In studies of children identified for renal hypodysplasia, 10% will have mutations in PAX2.21, 25, 26 Multicystic dysplastic kidney has been identified in 10% of reported cases. Oligomeganephronia refers to kidneys where nephron number is strikingly reduced with structurally intact nephrons except for compensatory glomerular hypertrophy.23 Ultrasound findings show increased echogenicity as well as small size for age.3 Histologic findings can include glomerulosclerosis and mesangial fibrosis1, 13 (Figure 3).

Figure 3 Histologic image of a single glomerlus from a patient with PAX2 mutation c.76dup exhibiting mesangial fibrosis and glomerulosclerosis.13 End-stage renal disease (ESRD) or renal failure can occur at any time, even within the same family with identical mutations in PAX2. ESRD may present prenatally with severely hypoplastic or aplastic kidneys and oligohydramnios resulting in fetal loss.18, 27 ESRD has been identified shortly after birth3, 18 and can occur as late as the seventh decade.12, 18 A single case of a surviving infant with Potter sequence, optic nerve malformations and a PAX2 mutation has been reported.28 Other renal findings include proteinuria, hypertension and vesicoureteral reflux. Vesicoureteral reflux may be an associated finding and although the majority may undergo spontaneous resolution, severe cases may be complicated by recurrent urinary tract infections and hydronephrosis necessitating surgical intervention.3, 18, 22 Auditory system High frequency hearing loss presenting in childhood can be identified in up to 10% of affected individuals.9 High frequency hearing loss is unusual in childhood. In embryogenesis, Pax2 expression is critical for cochlear development and loss of Pax2 expression in the otic placode in knockout mice results in complete loss of cochlear development.29 The high frequency hearing loss in RCS appears to be a significant recurrent observation rather than related to age-related hearing loss. Other clinical associations Ligamentous laxity has been observed in a number of patients, but the underlying mechanism is uncertain.3, 14, 18 Chiari 1 malformation has been identified in a single patient with a PAX2 mutation.14 There are three reported individuals with developmental disability, although the majority of patients with PAX2 mutations have normal intellect.13, 19, 30 Go to: Allelic Conditions Mutations in PAX2 have been identified in patients with isolated renal hypoplasia. In a series of 20 patients with renal hypoplasia, two were identified to have mutations in PAX2,25 one were subsequently found to have an optic nerve coloboma. In a study of children with renal hypoplasia, six out of ninety-nine probands were identified to have mutations in PAX2.21 In a recent survey of 20 children and young adults with congenital malformations of the urinary tract (CAKUT), two probands were identified to have PAX2 mutations and one subsequently was found to have optic nerve abnormalities.26