PAX2-Related Disorder

Clinical characteristics: PAX2-related disorder is an autosomal dominant disorder associated with renal and eye abnormalities. The disorder was originally referred to as renal coloboma syndrome and characterized by renal hypodysplasia and abnormalities of the optic nerve; with improved access to molecular testing, a wider range of phenotypes has been recognized in association with pathogenic variants in PAX2. Abnormal renal structure or function is noted in 92% of affected individuals and ophthalmologic abnormalities in 77% of affected individuals. Renal abnormalities can be clinically silent in rare individuals. In most individuals, clinically significant renal insufficiency / renal failure is reported. End-stage renal disease requiring renal transplant is not uncommon. Uric acid nephrolithiasis has been reported. Ophthalmologic abnormalities are typically described as optic nerve coloboma or dysplasia. Iris colobomas have not been reported in any individual with PAX2–related disorder. Ophthalmologic abnormalities may significantly impair vision in some individuals, while others have subtle changes only noted after detailed ophthalmologic examination. Additional clinical findings include high-frequency sensorineural hearing loss, soft skin, and ligamentous laxity. PAX2 pathogenic variants have been identified in multiple sporadic and familial cases of nonsyndromic renal disease including renal hypodysplasia and focal segmental glomerulosclerosis.

Diagnosis/testing: The diagnosis of PAX2-related disorder is established in a proband with the characteristic renal and/or eye findings by the identification of a heterozygous pathogenic variant in PAX2 by molecular genetic testing. Among individuals with apparently nonsyndromic renal hypodysplasia and in families with autosomal dominant isolated focal segmental glomerulosclerosis, pathogenic variants in PAX2 have been identified in approximately 8% and 4%, respectively.

Management: Treatment of manifestations: Ongoing treatment of hypertension and/or vesicoureteral reflux; renal replacement therapy (dialysis and/or renal transplantation) for end-stage renal disease; low vision aids for significant visual impairment.

Prevention of secondary complications: Use of protective eyewear to prevent retinal detachment.

Surveillance: Follow up by a nephrologist to monitor renal function and blood pressure and an ophthalmologist to monitor vision, with periodic audiometric evaluations.

Evaluation of relatives at risk: Offer molecular genetic testing if a PAX2 pathogenic variant has been identified in an affected family member. If no PAX2 pathogenic variant has been found, perform dilated ophthalmologic examination, renal ultrasound examination, tests of renal function, uric acid levels, and urinalysis; measure blood pressure.

Genetic counseling: PAX2-related disorder is inherited in an autosomal dominant manner. Approximately 65% of probands with a documented PAX2 pathogenic variant have a negative family history. In such cases, the negative family history may be explained by a de novo pathogenic variant, unrecognized symptoms in the parents, or parental germline mosaicism for a PAX2 pathogenic variant. Both maternal and paternal germline mosaicism, with unaffected parents having more than one affected child with a pathogenic variant, have been reported. Prenatal testing and preimplantation genetic testing are possible if the pathogenic PAX2 pathogenic variant has been identified in the family.