title: An unusual presentation of Denys-Drash syndrome due to bigenic disease.
abstract: We report a case of Denys-Drash syndrome (DDS) in a 3-month-old girl presenting with bilateral renal cortical cysts mimicking polycystic kidney disease. Genetic analysis revealed a de novo heterozygous missense mutation c.1186G>A (p.Asp396Asn) in the WT1 gene, confirming the diagnosis of DDS. Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1β, PAX2, PKD1, and PKD2. Remarkably, we identified a heterozygous missense variant c.12439A>G (p.Lys4147Glu) in the PKD1 gene. The same variant was found in the patient's mother, who had no renal cysts, and in the grandfather, who had several renal cysts. Mutation prediction programs classified the c.12439A>G variant as being "likely pathogenic." We hypothesize that the severe cystic phenotype in the index patient could be due to the WT1 mutation, enhancing pathogenicity of the "hypomorph" PKD1 allele. A possible role for Wilms tumor suppressor 1 (WT1) in renal cyst development should be considered. From a conceptual point of view, this case shows that an unusual presentation of a known genetic syndrome might point to bigenic inheritance, with unexpected interference of mutated genes causing an uncommon clinical phenotype.
authors.affiliation: Pediatric Nephrology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. benedicte.eneman@uzleuven.be.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Eneman
authors.forename: Djalila
authors.initials: D
authors.lastname: Mekahli
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Audrezet
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lerut
authors.forename: Rita
authors.initials: R
authors.lastname: Van Damme-Lombaerts
authors.forename: Lambertus
authors.initials: L
authors.lastname: Van den Heuvel
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
mesh_terms: D030321:Denys-Drash Syndrome / Q000175:diagnosis* / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D016162:Genes, Wilms Tumor; D005819:Genetic Markers; D006579:Heterozygote; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D016891:Polycystic Kidney, Autosomal Dominant / Q000175:diagnosis* / Q000235:genetics; D050396:TRPP Cation Channels / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D050396:TRPP Cation Channels
keywords: Denys-Drash syndrome; PKD1; WT1; diffuse mesangial sclerosis; polycystic kidney disease